Tetrahydropyridopyrazines as modulators of gpr6

ABSTRACT

The present invention provides compounds of formula I: 
     
       
         
         
             
             
         
       
     
     which are useful as modulators of GPR6, pharmaceutical compositions thereof, methods for treatment of conditions associated with GPR6, processes for making the compounds and intermediates thereof.

FIELD OF THE INVENTION

The present invention relates to medicinal chemistry, pharmacology, andmedicine.

BACKGROUND OF THE INVENTION

The present invention provides compounds that are G-Protein-CoupledReceptor 6 (hereinafter referred to as GPR6) modulators. GPR6 is GPCRthat signals via the Gs pathway. GPR6 receptors are highly expression inthe central nervous system (CNS), particularly medium spiny neurons(MSNs) of the striatum, with minimal expression in peripheral tissues.The major striatal targets of dopaminergic innervation reside in themedium spiny neurons (MSNs) of the striatopallidal (indirect) andstriatonigral (direct) output pathways. The MSNs of the direct outputpathway express D1 dopamine receptors whereas those in the indirectpathway express D2 receptors. GPR6 is enriched in D2 receptor expressingMSNs in the striatum where GPR6 activity is functionally opposed to D2receptor signaling. Antagonism or inverse agonism of Gs coupled GPR6decreases cAMP in MSNs and provides a functional alternative to dopaminemediated activation of D2 receptors. Therefore, the compounds of thepresent invention are useful to treat a variety of neurological andpsychiatric disorders, including Parkinson's disease.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

wherein

-   R₁ is selected from the group consisting of optionally substituted    C₃₋₈ cycloalkyl, optionally substituted C₃₋₆ heterocyclyl,    optionally substituted C₆₋₁₀ aryl, and optionally substituted C₁₋₁₀    heteroaryl;-   X₁ is N and X₂ is CH; or-   X₁ is CH and X₂ is N; or-   X₁ is N and X₂ is N;-   when X₁ is N, Z is selected from the group consisting of C₁₋₆    alkylene, C₁₋₆ haloalkylene, —C(O)—, and —S(O)₂—;-   when X₁ is CH, Z is selected from the group consisting of C₁₋₆    alkylene, C₁₋₆ haloalkylene, —O—, —C(O)—, —NH—, —S—, —S(O)—, and    —S(O)₂—;-   q is 0, 1, or 2;-   s is 0, 1, or 2;-   R₂ is —OR₅ or —NR₆R₇;-   R₃, each time taken, is independently selected from the group    consisting of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and trifluoromethyl;-   p is 0, 1, or 2;-   R₄, each time taken, is independently selected from the group    consisting of C₁₋₆ alkyl, hydroxy, and halo;-   r is 0 or 1;-   R₅ is selected from the group consisting of C₁₋₆ alkyl and C₃₋₈    cycloalkyl;-   R₆ is selected from the group consisting of hydrogen and C₁₋₆ alkyl;-   R₇ is selected from the group consisting of optionally substituted    C₁₋₆ alkyl, C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,    optionally substituted C₁₋₁₀ heteroaryl, and optionally substituted    C₃₋₆ heterocyclyl;-   X₃ is selected from the group consisting of CH and CR₄ and X₄ is    NR₈; or-   X₃ is NR₈ and X₄ is selected from the group consisting of CH and    CR₄;-   R₈ is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆    haloalkyl, C₃₋₈ cycloalkyl, —S(O)₂—R₉, —C(O)—R₁₀, —C(O)—N(R₁₁)(R₁₂),    and —C(O)—OR₁₃;-   R₉ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₈    cycloalkyl, and optionally substituted phenyl;-   R₁₀ is selected from the group consisting of hydrogen, optionally    substituted C₁₋₆ alkyl, C₃₋₈ cycloalkyl, optionally substituted    C₆₋₁₀ aryl, optionally substituted C₁₋₁₀ heteroaryl, and optionally    substituted C₃₋₆ heterocyclyl;-   R₁₁ is selected from the group consisting of hydrogen and C₁₋₆    alkyl;-   R₁₂ is selected from the group consisting of hydrogen, C₁₋₆ alkyl    and C₃₋₈ cycloalkyl; or-   R₁₁ and R₁₂ are taken together with the nitrogen to which they are    attached form a 4 to 7 membered, saturated, ring optionally having 1    additional ring heteroatom selected from the group N, O, and S and    optionally substituted on any of the ring carbon atoms with 1 to 5    substituents independently selected from the group consisting of    cyano, halo, hydroxy, amino, optionally substituted C₃₋₆    heterocyclyl, C₁₋₉ amide, optionally substituted C₁₋₆ alkyl, and    C₁₋₄ alkoxy and substituted on any additional ring nitrogen by a    substituent selected from the group consisting of hydrogen, C₃₋₈    cycloalkyl, and optionally substituted C₁₋₆ alkyl;-   R₁₃ is selected from the group consisting of C₁₋₆ alkyl and C₃₋₈    cycloalkyl; or a pharmaceutically acceptable salt thereof.

The present invention also provides pharmaceutical compositions,comprising: a compound of formula I or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable excipient.

The compounds of the present invention are modulators of GPR6 and areuseful to treat a variety of neurological and psychiatric disorders, forexample movement disorders including Parkinson's disease, levodopainduced dyskinesias, and Huntington's disease, drug addiction, eatingdisorders, cognitive disorders, schizophrenia, bipolar disorders, anddepression. Thus, the present invention also provides methods oftreating the conditions associated with GPR6 described hereincomprising, administering to a patient in need thereof an effectiveamount of the compounds of the invention. The present invention providesfor the use of the compounds of the invention as a medicament, includingfor treatment of the conditions associated with GPR6 described herein,and including for the manufacture of a medicament for treating theconditions associated with GPR6 described herein.

The present invention also provides processes from making GPR6modulators and intermediates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “C₁₋₄ alkyl” refers to a straight or branched alkyl chain ofone to four carbon atoms.

The term “optionally substituted C₁₋₄ alkyl” refers to a C₁₋₄ alkyloptionally substituted with 1 to 6 substituents independently selectedfrom the group consisting of optionally substituted C₁₋₄ alkoxy, C₁₋₄thioalkoxy, C₁₋₉ amide, C₁₋₇ amido, amino, C₁₋₈ alkylamino, C₁₋₅oxycarbonyl, C₁₋₅ carbonyloxy, C₁₋₈ sulfonyl, cyano, optionallysubstituted C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy, nitro,oxo, optionally substituted C₃₋₆ heterocyclyl, optionally substitutedC₁₋₁₀ heteroaryl, and optionally substituted C₆₋₁₀ aryl.

More particularly “optionally substituted C₁₋₄ alkyl” refers to a C₁₋₄alkyl optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, amino,C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo,hydroxy, C₃₋₆ heterocyclyl optionally substituted on any ring nitrogenby C₁₋₄ alkyl, C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

Even more particularly “optionally substituted C₁₋₄ alkyl” refers to aC₁₋₄ alkyl optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, cyano, C₃₋₈cycloalkyl, halo, hydroxy, C₃₋₆ heterocyclyl optionally substituted onany ring nitrogen by C₁₋₄ alkyl, and optionally substituted phenyl.

The term “C₁₋₆ alkyl” refers to a straight or branched alkyl chain ofone to six carbon atoms.

The term “optionally substituted C₁₋₆ alkyl” refers to a C₁₋₆ alkyloptionally substituted with 1 to 7 substituents independently selectedfrom the group consisting of amino, C₁₋₈ alkylamino, optionallysubstituted C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, C₁₋₉ amide, C₁₋₇ amido, C₁₋₅oxycarbonyl, C₁₋₅ carbonyloxy, C₁₋₈ sulfonyl, cyano, optionallysubstituted C₃₋₈ cycloalkyl, halo, hydroxy, oxo, optionally substitutedC₁₋₁₀ heteroaryl, optionally substituted C₃₋₆ heterocyclyl, andoptionally substituted C₆₋₁₀ aryl.

More particularly “optionally substituted C₁₋₆ alkyl” refers to a C₁₋₆alkyl optionally substituted with 1 to 7 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, amino,C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo,hydroxy, C₃₋₆ heterocyclyl optionally substituted on any ring nitrogenby C₁₋₄ alkyl, C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

Even more particularly “optionally substituted C₁₋₆ alkyl” refers to aC₁₋₆ alkyl optionally substituted with 1 to 7 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, cyano, C₃₋₈cycloalkyl, halo, hydroxy, C₃₋₆ heterocyclyl optionally substituted onany ring nitrogen by C₁₋₄ alkyl, and optionally substituted phenyl.

The term “C₁₋₆ haloalkyl” refers to a straight or branched alkyl chainof one to six carbon atoms substituted with 1 to 3 halogen atoms. Moreparticularly, the term “C₁₋₆ haloalkyl” refers fluoromethyl anddifluoromethyl.

The term “C₁₋₈ sulfonyl” refers to a sulfonyl linked to a C₁₋₆ alkylgroup, C₃₋₈ cycloalkyl, or an optionally substituted phenyl.

The term “C₁₋₆ alkylene” refers to a straight or branched, divalent,alkylene chain of one to six carbon atoms.

The term “C₁₋₆ haloalkylene” refers to a straight or branched, divalent,alkylene chain of one to six carbon atoms substituted with 1 to 3halogen atoms. More particularly, the term “C₁₋₆ haloalkylene” refersfluoromethylene and difluoromethylene.

The term “C₁₋₄ alkoxy” refers to a C₁₋₄ alkyl attached through an oxygenatom.

The term “optionally substituted C₁₋₄ alkoxy” refers to a C₁₋₄ alkoxyoptionally substituted with 1 to 6 substituents independently selectedfrom the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₅ oxycarbonyl,cyano, optionally substituted C₃₋₈ cycloalkyl, halo, hydroxy, optionallysubstituted C₁₋₁₀ heteroaryl, and optionally substituted C₆₋₁₀ aryl.While it is understood that where the optional substituent is C₁₋₄alkoxy or hydroxy then the substituent is generally not alpha to thealkoxy attachment point, the term “optionally substituted C₁₋₄ alkoxy”includes stable moieties and specifically includes trifluoromethoxy,difluoromethoxy, and fluoromethoxy.

More particularly “optionally substituted C₁₋₄ alkoxy” refers to a C₁₋₄alkoxy optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, cyano, C₃₋₈cycloalkyl, halo, hydroxy, and optionally substituted phenyl. Even moreparticularly “optionally substituted C₁₋₄ alkoxy” refers totrifluoromethoxy, difluoromethoxy, and fluoromethoxy.

The term “C₁₋₉ amide” refers to a —C(O)NR_(a)R_(b) group in which R_(a)is selected from the group consisting of hydrogen and C₁₋₄ alkyl, andR_(b) is selected from the group consisting of hydrogen, C₁₋₃ alkyl, andoptionally substituted phenyl.

The term “C₁₋₇ amido” refers to a —NHC(O)R_(c) group in which R_(c) isselected from the group consisting of hydrogen, C₁₋₆ alkyl, andoptionally substituted phenyl.

The term “C₁₋₅ carbamoyl” refers to an O- or N-linked carbamatesubstituted with a terminal C₁₋₄ alkyl.

The term “C₁₋₅ ureido” refers to a urea optionally substituted with aC₁₋₄ alkyl.

The term “C₁₋₈ alkylamino” refers to a —NR_(d)R_(e) group in which R_(d)is a C₁₋₄ alkyl and R_(e) is selected from the group consisting ofhydrogen and C₁₋₄ alkyl.

The term “C₆₋₁₀ aryl” refers to a monocyclic and polycyclic unsaturated,conjugated hydrocarbon having five to ten carbon atoms, and includesphenyl, and naphthyl.

More particularly “C₆₋₁₀ aryl” refers to phenyl.

The term “optionally substituted C₆₋₁₀ aryl” refers to a C₆₋₁₀ aryloptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of optionally substituted C₁₋₄ alkyl,optionally substituted C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₇ amido, C₁₋₅ oxycarbonyl, C₁₋₅ carbonyloxy,C₁₋₈ sulfonyl, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido, aminosulfonyl, C₁₋₁₀aminosulfonyl, C₁₋₅ ureido, cyano, halo, and hydroxyl.

More particularly “optionally substituted C₆₋₁₀ aryl” refers to a C₆₋₁₀aryl optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halo, hydroxy, amino, trifluoromethyl, and trifluoromethoxy.

Even more particularly “optionally substituted C₆₋₁₀ aryl” refers tophenyl optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halo, trifluoromethyl, and trifluoromethoxy.

The term “C₁₋₅ oxycarbonyl” refers to an oxycarbonyl group (—CO₂H) andC₁₋₄ alkyl ester thereof.

The term “C₁₋₅ carbonyloxy” refers to a carbonyloxy group (—O₂CR_(f)),in which R_(f) is selected from the group consisting of hydrogen andC₁₋₄ alkyl, for example, acetoxy.

The term “C₃₋₈ cycloalkyl” refers to monocyclic or bicyclic, saturatedor partially (but not fully) unsaturated alkyl ring of three to eightcarbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. It is understood that the term includesbenzofused cyclopentyl and cyclohexyl.

The term “optionally substituted C₃₋₈ cycloalkyl” refers to a C₃₋₈cycloalkyl optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,optionally substituted C₁₋₄ alkoxy, C₁₋₆ amide, C₁₋₂ amido, amino, C₁₋₈alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy,halo, hydroxy, nitro, oxo, optionally substituted C₁₋₁₀ heteroaryl, andoptionally substituted phenyl.

More particularly “optionally substituted C₃₋₈ cycloalkyl” refers to aC₃₋₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of C₁₋₄ alkoxy, halo,hydroxy, and C₁₋₄ alkyl optionally substituted with C₁₋₄ alkoxy, halo,and hydroxy.

The term “C₃₋₈ cycloalkoxy” refers to a C₃₋₈ cycloalkyl attached throughand oxygen.

The terms “halogen” and “halo” refers to a chloro, fluoro, bromo or iodoatom.

The term “C₃₋₆ heterocyclyl” refers to a 4 to 8 membered monocyclic orbicyclic, saturated or partially (but not fully) unsaturated ring havingone or two heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur and the ring optionally includes a carbonyl to form alactam or lactone. It is understood that where sulfur is included thatthe sulfur may be either —S—, —SO—, and —SO₂—. It is also under that theterm includes spirofused bicyclic systems. For example, but notlimiting, the term includes azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl,hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, and thelike. It is understood that a C₃₋₆ heterocyclyl can be attached as asubstituent through a ring carbon or a ring nitrogen atom.

More particularly “C₃₋₆ heterocyclyl” is selected from the groupconsisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, andtetrahydrofuryl.

The term “optionally substituted C₃₋₆ heterocyclyl” refers to a C₃₋₆heterocyclyl optionally substituted on the ring carbons with 1 to 4substituents independently selected from the group consisting ofoptionally substituted C₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy,C₁₋₉ amide, C₁₋₇ amido, amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano,optionally substituted C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy,nitro, oxo, and optionally substituted phenyl; and optionallysubstituted on any ring nitrogen with a substituent independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,C₃₋₈ cycloalkyl, optionally substituted C₃₋₆ heterocyclyl, optionallysubstituted C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

More particularly “optionally substituted C₃₋₆ heterocyclyl” refers to aC₃₋₆ heterocyclyl optionally substituted on the ring carbons with 1 to 4substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, halo, and hydroxy and optionally substituted on anyring nitrogen with a C₁₋₄ alkyl.

The term “C₁₋₁₀ heteroaryl” refers to a five to thirteen membered,monocyclic or polycyclic fully unsaturated, ring or ring system with oneto ten carbon atoms and one or more, typically one to four, heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur. Forexample, but not limiting, the term includes furyl, thienyl, pyrrolyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidyl, azepinyl, diazepinyl, benzazepinyl, benzodiazepinyl,benzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl,benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl,benzopyrazinyl, benzopyrazolyl, imidazopyridyl, pyrazolopyridyl,pyrrolopyridyl, quinazolyl, thienopyridyl, imidazopyridyl, quinolyl,isoquinolyl benzothiazolyl, and the like. It is understood that a C₁₋₁₀heteroaryl can be attached as a substituent through a ring carbon or aring nitrogen atom where such an attachment mode is available, forexample for a pyrrolyl, indolyl, imidazolyl, pyrazolyl, azepinyl,triazolyl, pyrazinyl, etc.

More particularly “C₁₋₁₀ heteroaryl” is selected from the groupconsisting of furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl,pyrazolyl, triazolyl, pyridyl, and pyrimidyl.

The term “optionally substituted C₁₋₁₀ heteroaryl” refers to a C₁₋₁₀heteroaryl optionally substituted with 1 to 5 substituents on carbonindependently selected from the group consisting of amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₇ amido, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido,aminosulfonyl, C₁₋₁₀ aminosulfonyl, C₁₋₅ ureido, optionally substitutedC₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy, cyano, halo, hydroxyl,oxo, nitro, C₁₋₅ carbonyloxy, C₁₋₅ oxycarbonyl, and C₁₋₈ sulfonyl andoptionally substituted with a substituent on each nitrogen independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,C₁₋₈ sulfonyl, optionally substituted C₃₋₆ heterocyclyl, and optionallysubstituted phenyl.

More particularly “optionally substituted C₁₋₁₀ heteroaryl” refers to aC₁₋₁₀ heteroaryl optionally substituted with 1 to 3 substituents oncarbon independently selected from the group consisting of amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halo, hydroxyl,oxo, trifluoromethyl, and trifluoromethoxy and optionally substituted ona ring nitrogen with a C₁₋₄ alkyl.

Even more particularly “optionally substituted C₁₋₁₀ heteroaryl” refersto a C₁₋₁₀ heteroaryl selected from the group consisting of furyl,thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, diazolyl,pyridyl, pyrimidyl, and triazolyl each optionally substituted with 1 to3 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, cyano, halo, trifluoromethyl, and trifluoromethoxyand optionally substituted on a ring nitrogen with a methyl.

The term “oxo” refers to an oxygen atom doubly bonded to the carbon towhich it is attached to form the carbonyl of a ketone or aldehyde. Forexample, a pryidone radical is contemplated as an oxo substituted C₁₋₁₀heteroaryl.

The term “optionally substituted phenyl” refers to a phenyl groupoptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amide, amino,C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxyl, nitro, C₁₋₈sulfonyl, and trifluoromethyl.

More particularly “optionally substituted phenyl” refers to a phenylgroup optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxyl, nitro,and trifluoromethyl.

The term “C₁₋₆ sulfonylamido” refers to a —NHS(O)₂—R_(g) group whereinR_(g) is selected from the group consisting of C₁₋₆ alkyl and optionallysubstituted phenyl.

The term “aminosulfonyl” refers to a —S(O)₂NH₂.

The term “C₁₋₁₀ aminosulfonyl” refers to a —S(O)₂NR_(h)R_(i) groupwherein R_(h) is selected from the group consisting of hydrogen and C₁₋₄alkyl and R_(i) is selected from the group consisting of C₁₋₄ alkyl, andoptionally substituted phenyl.

The term “C₁₋₄ thioalkoxy” refers to a C₁₋₄ alkyl attached through asulfur atom.

The term “pharmaceutically acceptable salt” refers to salts ofpharmaceutically acceptable organic acids and bases or inorganic acidsand bases. Such salts are well known in the art and include thosedescribed in Journal of Pharmaceutical Science, 66, 2-19 (1977). Anexample is the hydrochloride salt.

The term “substituted,” including when used in “optionally substituted”refers to one or more hydrogen radicals of a group are replaced withnon-hydrogen radicals (substituent(s)). It is understood that thesubstituents may be either the same or different at every substitutedposition. Combinations of groups and substituents envisioned by thisinvention are those that are stable or chemically feasible.

The term “stable” refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production. In anon-limiting example, a stable compound or chemically feasible compoundis one that is not substantially altered when kept at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for about a week.

It is understood that, where the terms defined herein mention a numberof carbon atoms, the mentioned number refers to the mentioned group anddoes not include any carbons that may be present in any optionalsubstituent(s) thereon.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as isomers. All stereoisomers of the compoundsof the invention, including geometric isomers, enantiomers, anddiastereomers, in any ratio, are contemplated to be within the scope ofthe present invention.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as tautomers. All tautomeric forms the compoundsof the invention are contemplated to be within the scope of the presentinvention.

Compounds of the invention also include all pharmaceutically acceptableisotopic variations, in which at least one atom is replaced by an atomhaving the same atomic number, but an atomic mass different from thepredominant atomic mass. Isotopes suitable for inclusion in compounds offormula I include radioactive isotopes.

The terms “compounds of the invention” and “a compound of the invention”and “compounds of the present invention, and the like include theembodiment of formula I and the other more particular embodimentsencompassed by formula I described herein and exemplified compoundsdescribed herein and a pharmaceutically acceptable salt of each of theseembodiments.

The present invention provides a compound of formula II:

wherein

-   R₁ is selected from the group consisting of optionally substituted    C₃₋₈ cycloalkyl, optionally substituted C₃₋₆ heterocyclyl,    optionally substituted C₆₋₁₀ aryl, and optionally substituted C₁₋₁₀    heteroaryl;-   X₁ is N and X₂ is CH; or-   X₁ is CH and X₂ is N; or-   X₁ is N and X₂ is N;-   when X₁ is N, Z is selected from the group consisting of C₁₋₆    alkylene, C₁₋₆ haloalkylene, —C(O)—, and —S(O)₂—;-   when X₁ is CH, Z is selected from the group consisting of C₁₋₆    alkylene, C₁₋₆ haloalkylene, —O—, —C(O)—, —NH—, —S—, —S(O)—, and    —S(O)₂—;-   q is 0, 1, or 2;-   s is 0, 1, or 2;-   R₂ is —OR₅ or —NR₆R₇;-   R₃, each time taken, is independently selected from the group    consisting of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and trifluoromethyl;-   p is 0, 1, or 2;-   R₄, each time taken, is independently selected from the group    consisting of C₁₋₆ alkyl, hydroxy, and halo;-   r is 0 or 1;-   R₅ is selected from the group consisting of C₁₋₆ alkyl and C₃₋₈    cycloalkyl;-   R₆ is selected from the group consisting of hydrogen and C₁₋₆ alkyl;-   R₇ is selected from the group consisting of optionally substituted    C₁₋₆ alkyl, C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,    optionally substituted C₁₋₁₀ heteroaryl, and optionally substituted    C₃₋₆ heterocyclyl;-   X₅ is selected from the group consisting of CH and CR₄ and X₆ is    selected from the group consisting of NH and N—CH₂-(optionally    substituted phenyl); or-   X₅ is selected from the group consisting of NH and N—CH₂-(optionally    substituted phenyl) and X₆ is selected from the group consisting of    CH and CR₄;-   or a pharmaceutically acceptable salt thereof.

(Ia) One embodiment relates to compounds of formula I wherein X₁ is CHand X₂ is N.

(Ib) One embodiment relates to compounds of formula I wherein X₁ is Nand X₂ is N.

(Ic) One embodiment relates to compounds of formula I and embodiment(Ia) and (Ib) wherein X₃ is selected from the group consisting of CH andCR₄ and X₄ is NR₈.

(Id) One embodiment relates to compounds of formula I and embodiment(Ia) and (Ib) wherein X₃ is NR₈ and X₄ is selected from the groupconsisting of CH and CR₄.

(Ie) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), and (Id) wherein R₁ is optionally substituted C₆₋₁₀aryl.

(If) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), and (Id) wherein Z is C₁₋₆ alkylene.

(Ig) One embodiment relates to compounds formula I and embodiments (Ia),(Ib), (Ic), and (Id) wherein Z is C₁₋₆ haloalkylene.

(Ih) One embodiment relates to compounds formula I and embodiments (Ia),(Ic), and (Id) wherein Z is —O—.

(Ii) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), and (Id) wherein Z is —C(O)—.

(Ij) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ii) whereinR₂—NR₆R₇. In another embodiment within embodiment (Ij), R₆ is hydrogenand R₇ is C₁₋₆ alkyl. In yet another embodiment within embodiment (Ij),R₆ is hydrogen and R₇ is C₃₋₈ cycloalkyl. In yet another embodimentwithin embodiment (Ij), R₆ is hydrogen and R₇ is C₃₋₆ heterocyclyl.

(Ik) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), and (Ij) wherein sis 1.

(Il) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik)wherein q is 1.

(Im) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), and(Il) wherein R₈ is selected from the group consisting —C(O)—R₁₀,—C(O)—N(R₁₁)(R₁₂), and —C(O)—OR₁₃.

(In) One embodiment relates to compounds of formula I and embodiments(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), and(Il) wherein R₈ is —(O)—R₁₀ and R₁₀ is C₁₋₆ alkyl.

(IIa) One embodiment relates to compounds of formula II wherein X₁ is CHand X₂ is N.

(IIb) One embodiment relates to compounds of formula II wherein X₁ is Nand X₂ is N.

(IIc) One embodiment relates to compounds of formula II and embodiment(IIa) and (IIb) wherein X₃ is NR₈ and X₄ is selected from the groupconsisting of CH and CR₄.

(IId) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), and (IIc) wherein R₁ is optionally substituted C₆₋₁₀ aryl.

(IIe) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIc), and (IId) wherein Z is C₁₋₆ alkylene.

(IIf) One embodiment relates to compounds formula II and embodiments(IIa), (IIb), (IIc), and (IId) wherein Z is C₁₋₆ haloalkylene.

(IIg) One embodiment relates to compounds formula II and embodiments(IIa), (IIc), and (IId) wherein Z is —O—.

(IIh) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIc), and (IId) wherein Z is —C(O)—.

(IIi) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), and (IIh) whereinR₂—NR₆R₇. In another embodiment within embodiment (IIj), R₆ is hydrogenand R₇ is C₁₋₆ alkyl. In yet another embodiment within embodiment (IIj),R₆ is hydrogen and R₇ is C₃₋₈ cycloalkyl. In yet another embodimentwithin embodiment (IIj), R₆ is hydrogen and R₇ is C₃₋₆ heterocyclyl.

(IIj) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), and (IIi)wherein s is 1.

(IIk) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), and (IIj)wherein q is 1.

(IIl) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), and (IIk)wherein X₅ is selected from the group consisting of CH and CR₄ and X₆ isNH.

(IIm) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), and (IIk)wherein X₅ is selected from the group consisting of NH X₆ is selectedfrom the group consisting of CH and CR₄.

(IIn) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), and (IIk)wherein X₅ is selected from the group consisting of CH and CR₄ and X₆ isN—CH₂-(optionally substituted phenyl).

(IIo) One embodiment relates to compounds of formula II and embodiments(IIa), (IIb), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), and (IIl)wherein X₅ is selected from the group consisting of CH and CR₄ and X₆ isN—CH₂-(optionally substituted phenyl).

(ay) Another embodiment relates to a pharmaceutically acceptable salt ofeach of the above embodiments.

(az) Another embodiment relates to a pharmaceutically acceptable salt ofeach of the exemplified compounds.

The compounds of the invention can be prepared by a variety ofprocedures, some of which are described below. All substituents, unlessotherwise indicated, are as previously defined. The products of eachstep can be recovered by conventional methods including extraction,evaporation, precipitation, chromatography, filtration, trituration,crystallization, and the like. The procedures may require protection ofcertain groups, for example hydroxy, amino, or carboxy groups tominimize unwanted reactions. The selection, use, and removal ofprotecting groups are well known and appreciated as standard practice,for example T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Chemistry (John Wiley and Sons, 1991). In the schemes belowstarting materials are either commercially available or can be readyprepared by methods well known in the art.

Scheme A depicts the formation of compounds in which X₂ is N.

In Scheme A, step 1, an appropriate compound of formula 1 is contactedwith an appropriate compound of formula 2 to give a compound of formula3. An appropriate compound of formula 1 is one in which Hal is a halogenand R₄ and r are as desired in the final compound of formula I. Anappropriate compound of formula 2 is one in which R₁, Z, R₃, p, s, and qare as desired in the final compound of formula I or give rise to R₁, Z,and R₃ as desired in the final compound of formula I. Compounds offormula 2 are either commercially available or they can be readilyprepared by methods well known in the art. For example, compounds offormula 2 where Z is oxygen can be prepared by Mitsunobu reactionbetween a piperidinol and an aryl alcohol.

The reaction is carried out in a suitable organic solvent like dioxane,n-butanol, dimethyl sulfoxide and the like with or without base such asdiisopropylethylamine and triethylamine The reaction is generallycarried out at a temperature of from 0 to 80° C.

It is understood that a compound of formula 1 can also be treated withpiperazine to give rise to compounds in which X₁ is N. The piperazinederivative can be further modified by reductive amination, alkylation,arylation, amidation, sulfonylation and the like to provide a compoundof formula 3. Also the piperazine can be protected and elaborated asmentioned above after deprotection in a later step if desired.

In Scheme A, step 2, a compound of formula 3 is contacted with anappropriate compound of formula 4 to give a compound of formula 6 inwhich X_(3′) and X_(4′) give rise to X₃ and X₄ as desired in the finalproduct of formula I. An appropriate compound of formula 4 is HOR₅ orHNR₆R₇ in which R₅ or R₆ and R₇ are as desired in the final compound offormula I.

Where the compound of formula 4 is an amine, HNR₆R₇, the reaction iscarried out in a suitable organic solvent like dioxane, ethanol,tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide and the like,with or without a base such as sodium hydroxide, diisopropylethylamineor triethylamine. The reaction is generally carried out at temperaturebetween 20 to 150° C.

Where the compound of formula 4 is an alcohol, HOR₅, the reaction iscarried out in a suitable organic solvent like dioxane, tetrahydrofuran,dimethyl sulfoxide, N,N-dimethylformamide and the like, with a base suchas sodium hydride, lithium hydride, potassium t-butoxide, and the like.The reaction is generally carried out at temperature between 0 to 150°C.

Alternatively, as depicted in Scheme A, step 3, using the methodologydescribed above, an appropriate compound of formula 1 can be contactedwith an appropriate compound of formula 2 to give a compound of formula5. As depicted in Scheme A, step 4, a compound of formula 5 can becontacted with a compound of formula 2 to give a compound of formula 6.

In Scheme A, step 5, a compound of formula 6 is partially reduced to acompound of formula 7 in which the variables are defined above andX_(5′) is selected from the group consisting of CH, CR₄ and NH andX_(6′) is selected from the group consisting of CH, CR₄ and NH providedthat one of X_(5′) or X_(6′) is NH and the other is CH or CR₄.

Such partial reductions are well known in the art. The reaction iscarried out in a suitable organic solvent like dioxane, ethanol,methanol, isopropanol, tetrahydrofuran, and the like. The reaction isgenerally carried out using hydrogen and a catalyst, such as platinum orpalladium catalyst.

In Scheme A, step 6, a compound of formula 7 is alkylated,cycloalkylated, sulfonated, acylated, or converted to a urea orcarbamate using appropriate reagents that give R₈ being C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, —S(O)₂—R₉, —(O)—R₁₀, —C(O)—N(R₁₁)(R₁₂), or—C(O)—OR₁₃ as desired in the final compound of formula I. Suchtransformation are readily carried out by reductive amination,alkylation, sulfonylation, amide forming reactions, urea formingreactions, and carbamylation conditions that are well known in the art.

It will be recognized by one of ordinary skill in the art that the stepsin Scheme A may be varied to provide compounds of formula I. Inparticular, the order of the steps required to produce the compounds offormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. Other variations are possible and are readily understood bythe skilled person.

An example of a variation of Scheme A is depicted in Scheme B below.

Scheme B depicts the formation of compounds in which X₂ is N.

In Scheme B, step 1, an appropriate compound of formula 5 or 3, asprovided above, is partially reduced to a compound of formula 8 or 9,respectively. Such partial reductions are described above in Scheme A,step 5. In one embodiment the present invention provides compounds offormula 8 in which Hal is halogen and R₂, R₄, and r are as described forformula I. In another embodiment the present invention providescompounds of formula 9 in which Hal is halogen and R₁, Z, R₃, R₄, p, r,q, and s are s described for formula I.

In Scheme B, step 2, an appropriate compound of formula 8 or 9 isprotected to give compounds of formulae 10 or 11, respectively, in whichPg is an amine protecting group. The selection, use, and removal ofprotecting groups are well known and appreciated as standard practice,for example T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Chemistry (John Wiley and Sons, 1991). In one embodiment thepresent invention provides compounds of formula 10 in which Pg is—CH₂-(optionally substituted phenyl) and R₂, R₄, and r are as describedfor formula I. In another embodiment the present invention providescompounds of formula 11 in which Pg is —CH₂-(optionally substitutedphenyl) and R₁, Z, R₃, R₄, p, r, q, and s are s described for formula I.In another embodiment of the embodiments of formulae 10 and 11 is one inwhich Pg is benzyl.

In Scheme B, step 3, a compound of formula 10 is contacted with anappropriate compound of formula 2, as described above, to give acompound of formula 12 in which X_(5″) is a protected amine and X_(6″)is CH or CR₄. The reaction is carried out as described in Scheme A, step1.

In Scheme B, step 4, a compound of formula 11 is contacted with anappropriate compound of formula 4 to give a compound of formula 12 inwhich X_(5″) is CH or CR₄ and X_(6″) is a protected amine An appropriatecompound of formula 4 as described above. The reaction is carried out asdescribed in Scheme A, step 2.

In Scheme B, step 5, a compound of formula 12 is deprotected to give acompound of formula 7 as described above.

In Scheme B, step 6, a compound of formula 7 is alkylated,cycloalkylated, sulfonated, acylated, or converted to a urea orcarbamate using appropriate reagents that give R₈ being C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, —S(O)₂—R₉, —(O)—R₁₀, —C(O)—N(R₁₁)(R₁₂), or—C(O)—OR₁₃ as desired in the final compound of formula I as described inScheme A, step 6, above.

Scheme C depicts the formation of compounds in which X₂ is CH.

In Scheme C, step 1, an appropriate compound of formula 1, as describedabove, is contacted with an appropriate compound of formula 13 to give acompound of formula 9. An appropriate compound of formula 13 is one inwhich R₁, Z, R₃, p, s, and q are as desired in the final compound offormula I or give rise to R₁, Z, and R₃ as desired in the final compoundof formula I and Y a boronic acid or boronic ester. It is alsounderstood that the group depicted as R₁—Z— can be replaced by anappropriate protecting group, such a methyl, benzyl, t-BOC, or Cbz,subsequent removal of the protecting group and installation of R₁—Z— asdesired in the final product of formula I.

Such reactions are generally known as a Suzuki reaction and are wellknown in the art. While a Suzuki reaction is depicted in Scheme C it isunderstood that other carbon-carbon bond forming coupling reactions canbe used with compounds of formula 13 having Y other than boronic acid oresters to produce compounds of formula I.

In Scheme C, step 2, a compound of formula 14 is contacted with anappropriate compound of formula 4 to give a compound of formula 15. Anappropriate compound of formula 4 and general reaction conditions aredescribed above in Scheme A, step 2.

Alternately, Scheme C, step 3, depicts Suzuki reaction with anappropriate compound of formula 13 and an appropriate compound offormula 5 as described above to give a compound of formula 15.

In Scheme C, step 4, a compound of formula 15 is reduced to a compoundof formula 11 in which the variables are defined above and X_(5′) isselected from the group consisting of CH, CR₄ and NH and X_(6′) isselected from the group consisting of CH, CR₄ and NH provided that oneof X_(5′) or X_(6′) is NH and the other is CH or CR₄. The conditions aresimilar to those described above for Scheme A, step 7.

In Scheme C, step 5, a compound of formula 7 is alkylated,cycloalkylated, sulfonated, acylated, or converted to a urea orcarbamate using appropriate reagents that give R₈ being C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, —S(O)₂—R₉, —(O)—R₁₀, —C(O)—N(R₁₁)(R₁₂), or—C(O)—OR₁₃ as desired in the final compound of formula I. Suchtransformations are readily carried out by reductive amination,alkylation, sulfonylation, amide forming reactions, amidation, andcarbamylation conditions that are well known in the art.

It will be recognized by one of ordinary skill in the art that the stepsin Scheme C may be varied to provide compounds of formula I. Inparticular, the order of the steps required to produce the compounds offormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. For example, a compound of formula 9 or 5 can undergo step 4and the NH of X_(3′) or X_(4′) can be protected, followed beingcontacted with a compound of formula 13 or 4 to give a compound offormula 11 which as depicted above can be elaborated to a compound offormula I. Alternately, the double bond of the ring bearing R₁—Z— may bereduced separately from the partial reduction of the ring ultimatelybearing X₃ and X₄. Other variations are possible and are readilyunderstood by the skilled person.

It is also understood that some compounds of formula I may be elaboratedto other compounds of formula I, in an additional steps not shown.Compounds of formula I may be elaborated in a variety of ways. Suchreactions include hydrolysis, oxidation, reduction, alkylation,amidations, and the like. Also, in an optional step, not shown in theschemes above, the compounds of formula I can be converted topharmaceutically acceptable salts by methods well known and appreciatedin the art.

The following examples are intended to be illustrative and non-limiting,and represent specific embodiments of the present invention.

Proton nuclear magnetic resonance (NMR) spectra were obtained for manyof the compounds in the following examples. Characteristic chemicalshifts (δ) are given in parts-per-million downfield fromtetramethylsilane using conventional abbreviations for designation ofmajor peaks, including s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet), and br (broad). Other abbreviations have theirusual meaning unless otherwise indicated. The mass spectra, unlessotherwise indicated, were recorded using either electrospray ionization(ESI) or atmospheric pressure chemical ionization.

The examples below were carried out in appropriate vessels and weretypically stirred. Where indicated, products of certain preparations andexamples are purified by HPLC. Where indicated products of thepreparations and examples were purified by HPLC.

HPLC Method A: Pump: Shimadzu LC-8A; UV/Vis: SPD-20A; Software:LCSolution. A Phenomenex Gemini® C18, 5 μm, ID 30×100 mm column was usedand eluted with gradients of ACN (containing 0.035% TFA) and water(containing 0.005% TFA). A 10% to 100% ACN gradient was used unlessotherwise indicated.

HPLC Method B: Pump: Waters 2525 or 2545; MS: ZQ; Software: MassLynx. AXbridge™ C18, 5 μm, ID 30×75 mm column was used and eluted withgradients of ACN (containing 0.035% TFA) and water (containing 0.005%TFA).

After isolation by chromatography, the solvent is removed and theproduct is obtained by evaporating product containing fractions (e.g.,GeneVac™), rotary evaporator, evacuated flask, lyophilization, etc.

The abbreviations used throughout have their conventional meaningsunless indicated otherwise. For example, the following abbreviations areused: ACN (acetonitrile); aq (aqueous); Boc or t-BOC(tert-butoxycarbonyl); Cbz (carbobenzyloxy); DCM (dichloromethane); DMSO(dimethyl sulfoxide); TFA (trifluoroacetic acid); HOAc (acetic acid),MeOH (methanol), PE (petroleum ether), EA or EtOAc (ethyl acetate) andthe like.

Preparation 1 (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone

A solution of 2-bromo-4-chloro-1-fluorobenzene (175 μL, 1.377 mmol) inTHF (4.59 mL) at −78° C. was treated with n-BμLi (2.6 M, 741 μL, 1.928mmol) and the reaction mixture was stirred for 30 min. To this was addedtert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 mg,0.918 mmol) in one portion. The cooling bath was removed and theresulting reaction mixture was allowed to warm to rt and stirred for 1.5h. Purification by automated flash silica gel chromatography using 10%EtOAc in hexanes afforded tert-butyl4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 92%) asa yellow oil. ESI-MS m/z [M+Na]⁺ 364.20.

A solution of tert-butyl4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 0.843mmol) in dioxane (2.41 mL) was treated with HCl (2.11 mL, 8.43 mmol) atrt and the resulting reaction mixture was stirred overnight. Thereaction mixture was diluted with hexanes and filtered by suction toafford (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone as its HClsalt (146 mg, 62.3%) as a yellow solid. ESI-MS m/z [M+H]⁺ 242.20.

Preparation 2 4-(2,4-difluorophenoxy)piperidine

To a solution of 2,4-difluorophenol (10 g, 77 mmol), PPh₃ (30.2 g, 115mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (30.9 g, 154mmol) in THF (400 mL) was added DEAD (18.3 mL, 115 mmol) at 0° C.dropwise. After the addition was completed, the resulting mixture wasallowed to stir at 40° C. for 16 h. The mixture was poured into waterand extracted with EtOAc (3×400 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated to give the crude product.Purification by flash silica gel chromatography, eluting with 80:1PE:EtOAc, gave tert-butyl4-(2,4-difluorophenoxy)piperidine-1-carboxylate as an oil (20 g, 83%).

A solution of tert-butyl 4-(2,4-difluorophenoxy)piperidine-1-carboxylate(20 g, 63.8 mmol) in 4:1 HCl/EtOAc (250 mL) was stirred at 25° C. for 1h. The mixture was concentrated to give the title compound, as its HClsalt, as a white solid (15.4 g, 97%). ¹H NMR (400 MHz, DMSO-d6) δ ppm1.84 (m, 2H), 2.08 (m, 2H), 3.05 (m, 2H), 3.20 (m, 2H), 4.57 (m, 1H),7.04 (m, 1H), 7.31 (m, 2H), 8.95 (br d, 2H).

Preparation 3 3-fluoro-4-(piperidin-4-yloxy)benzonitrile

A solution of 3,4-difluorobenzonitrile (28 g, 201 mmol) and tert-butyl4-hydroxypiperidine-1-carboxylate (40.5 g, 201 mmol) in THF (500 mL) wastreated with sodium hydride (4 g, 100 mmoL) and stirred at 25° C. for 16h. The reaction mixture was washed with water, extracted with EtOAc, andthe crude product purified by flash silica gel chromatography gavetert-butyl 4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylate (25 g,39%).

A solution of tert-butyl4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylate (42 g, 131 mmol)dissolved in 4:1 HCl/EtOAc (100 mL) was stirred for 5 h. The mixture wasconcentrated to give the title compound as its HCl salt (12 g, 36%). ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.89 (m, 2H), 2.14 (m, 2H); 3.08 (m, 2H),3.21 (m, 2H), 4.86 (m, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz,1H), 7.89 (m, 1H); ESI-MS m/z [M+H]+ 220.7.

Preparation 4 6 4-((2,4-difluorophenyl)fluoromethyl)piperidine

To a 0° C. solution of tert-butyl4-(2,4-difluorobenzoyl)piperidine-1-carboxylate (1.28 g, 3.93 mmol) inMeOH (15.7 mL) was added NaBH₄ (0.372 g, 9.84 mmol). The ice bath wasremoved and the reaction mixture stirred for 2 h at room temperaturethen was quenched with saturated aqueous NH₄Cl. The organic layer wasextracted with EtOAc, washed with H₂O and dried over MgSO₄. The solventwas removed under reduced pressure gave tert-butyl4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate as awhite hygroscopic solid.

To a −78° C. solution of tert-butyl4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (200 mg,0.611 mmol) in DCM (3.055 mL) was added DAST (242 μL, 1.833 mmol). Themixture was stirred at −78° C. for 30 min, then quenched with MeOH.Flash silica gel chromatography using a gradient of 0% to 100% EtOAc inhexanes gave tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate as acolorless oil.

To a solution of racemic tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate (148 mg,0.449 mmol) in dioxane (1.50 mL) was added HCl (4 M in dioxane, 337 μL,1.348 mmol). The mixture was heated at 45° C. for 16 h then concentratedin vacuo to give the title compound as its HCl salt (109 mg, 91%) as awhite solid.

Preparation 5 (R)-4-((2,4-difluorophenyl)fluoromethyl)piperidinetert-Butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylateas a Colorless Oil

tert-Butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylatewas subjected to chiral SFC separation to give (R)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate.

(R)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate (2.8 g,8.50 mmol) was dissolved in EtOAc (20 mL) and HCl (4 M in EtOAc, 21 mL)was added. The reaction mixture was stirred at 23° C. for 2 h.Evaporation of the solvent gave the title compound as its HCl salt (2.1g, 93%). ESI-MS m/z [M+H]⁺ 229.9.

Preparation 6 (S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine

tert-Butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylateas was subjected to chiral SFC separation to give (R)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate.

The HCl salt of the title compound was prepared in similar fashion toPreparation 5a, using (S)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate. ESI-MS m/z[M+H]⁺ 229.9.

Preparation 7 4-((2-fluorophenyl)sulfonyl)piperidine

A mixture of 2-fluorobenzenethiol (0.764 mL, 7.15 mmol), tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), andK₂CO₃ (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C.overnight. The reaction mixture was poured into water and extractedtwice with EtOAc. The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure gave tert-butyl4-((2-fluorophenyl)thio)piperidine-1-carboxylate as a yellow oil (1.98g, 98%), which was carried forward without purification.

A solution of tert-butyl4-((2-fluorophenyl)thio)piperidine-1-carboxylate (1.98 g, 6.36 mmol) inTHF (54.5 mL) and MeOH (18.2 mL) at 0° C. was treated with a coldsolution of Oxone® (9.77 g, 15.9 mmol) in water (54.5 mL). The reactionmixture was stirred for 5 h, gradually warming to room temperature. Thereaction mixture was poured into water and extracted twice with EtOAc.The combined organics were washed with water and then saturated aqueousNaCl, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash silica gel chromatographyusing a gradient of 10% to 50% EtOAc with 0.1% triethylamine in heptanesgave tert-butyl 4-((2-fluorophenyl)sulfonyl)piperidine-1-carboxylate asa pale yellow oil (1.31 g, 60%).

A solution of tert-butyl4-((2-fluorophenyl)sulfonyl)piperidine-1-carboxylate (1.31 g, 3.82 mmol)in dioxane (12.7 mL) at room temperature was treated with 4M HCl indioxane (9.55 ml, 38.2 mmol). The reaction mixture was allowed to stirat room temperature overnight. The reaction mixture was concentratedunder reduced pressure. The resulting white solid was triturated withhexanes, filtered, collected, and lyophilized overnight to give thetitle compound, as its HCl salt, as a white solid (815.1 mg, 76%).ESI-MS m/z [M+H]⁺ 243.95.

Preparation 8 4-((2-fluoro-4-methoxyphenyl)sulfonyl)piperidine

A mixture of 2,4-difluorobenzenethiol (0.810 mL, 7.15 mmol), tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), andK₂CO₃ (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C.overnight. The reaction mixture was poured into water and extractedtwice with EtOAc. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford tert-butyl4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as ayellow oil, which was carried forward without purification.

A solution of tert-butyl4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g, 6.50mmol) in THF/MeOH (3:1, 74 mL) at 0° C. was treated with a cold solutionof Oxone® (9.99 g, 16.25 mmol) in water (56 mL). The reaction mixturewas allowed to stir overnight, gradually warming to room temperature.The reaction mixture was poured into water and extracted twice withEtOAc. The combined organics were washed with water and then saturatedaqueous NaCl, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash silica gelchromatography using a gradient of 10% to 40% EtOAc with 0.1%triethylamine in heptanes gave tert-butyl4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (1.32 g, 56%)as a white solid. ESI-MS m/z [M+Na]⁺ 383.80.

To a suspension of tert-butyl4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (50 mg, 0.138mmol) in MeOH (461 μL) was added sodium methoxide (25.6 μL, 0.138 mmol,5.4 M in MeOH) dropwise. The reaction mixture was allowed to stir at 45°C. for 20 min then concentrated in vacuo. Boc deprotection was carriedout by addition of HCl (138 μL, 0.553 mmol, 4 M in dioxane) to the crudereaction mixture in 300 μL dioxane. Stirring at 50° C. for 24 h followedby concentration in vacuo yielded the title compound as its HCl salt (57mg) as a white solid (10:1 regioisomeric mixture). ESI-MS m/z [M+H]⁺274.00.

Preparation 9 4-((3-fluorophenyl)sulfonyl)piperidine

A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate(1.0 g, 3.58 mmol), K₂CO₃ (0.742 g, 5.37 mmol), and 3-fluorobenzenethiol(0.363 mL, 4.30 mmol) in ACN (7.5 mL) was stirred at 23° C. for 5 min.The reaction mixture was stirred at 80° C. for 17 h, cooled to 23° C.and partitioned between EtOAc and water. The layers were separated, theorganic phase was washed with brine, dried over Na₂SO₄, filtered, rinsedwith EtOAc, and dried in vacuo gave tert-butyl4-((3-fluorophenyl)thio)piperidine-1-carboxylate (1.115 g, 100%) as ayellow oil. ESI-MS m/z [M+H]⁺ 255.9.

A mixture of basic alumina (3.0 g, 29.4 mmol) in water (0.6 mL) wasstirred at 23° C. for 5 min. Next, ACN (12 mL) was added followed by asolution of tert-butyl 4-((3-fluorophenyl)thio)piperidine-1-carboxylate(1.115 g, 3.58 mmol) in CHCl₃ (8 mL). Next, Oxone® (6.60 g, 10.74 mmol)was added and the reaction mixture was stirred at 60° C. for 19 h. Thereaction mixture was cooled to 23° C., filtered, rinsed with CHCl₃, andthe filtrate was washed with water (10 mL). The organic layer was driedover Na₂SO₄, filtered, rinsed with CHCl₃, and dried in vacuo. The cruderesidue was dissolved in toluene (5 mL) and purified via medium pressurechromatography using a gradient of 10% to 100% EtOAc with 0.1%triethylamine in heptane on a 80 g silica gel column (Single Step™) gavetert-butyl 4-((3-fluorophenyl)sulfonyl)piperidine-1-carboxylate (0.769g, 62.5%) as a white solid. ESI-MS m/z [M+Na]⁺ 365.9.

To a solution of tert-butyl4-((3-fluorophenyl)sulfonyl)piperidine-1-carboxylate (756 mg, 2.201mmol) in dioxane (5.0 mL) was added HCl (4 M in dioxane, 5.50 mL, 22.01mmol) at 23° C. The reaction was stirred at 23° C. for 21 h to furnish awhite suspension. The resulting solid was filtered, rinsed with dioxaneand dried in vacuo to give the title compound as its HCl salt (582.6 mg,95%) as a white solid. ESI-MS m/z [M+H]⁺ 243.9.

Preparation 10 4-((3-methoxyphenyl)sulfonyl)piperidine

The title compound as its HCl salt was prepared in a similar manner toPreparation 11, with the exception that additional chloroform was usedin place of ACN in the second step. ESI-MS m/z [M+H]⁺ 255.9.

Preparation 12 4-((4-fluorophenyl)sulfonyl)piperidine

A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate(1.42 g, 5.08 mmol), 4-fluorobenzenethiol (0.663 ml, 6.10 mmol) andK₂CO₃ (1.054 g, 7.62 mmol) in ACN (12.71 mL) was stirred at 85° C.overnight. The reaction mixture was filtered by suction and the solventremoved gave tert-butyl 4-((4-fluorophenyl)thio)piperidine-1-carboxylate(1.5 g, 95%) as a white solid.

A solution of tert-butyl4-((4-fluorophenyl)thio)piperidine-1-carboxylate (1.5 g) in water (16.06mL) and MeOH (16.06 mL) was treated with Oxone® (5.92 g, 9.63 mmol) atroom temperature and the resulting reaction mixture was stirred for 6 h.The solution was filtered by suction and the solvent removed gavetert-butyl 4-((4-fluorophenyl)sulfonyl)piperidine-1-carboxylate (1.6 g,4.66 mmol, 97% yield) as a white solid.

A solution of tert-butyl4-((4-fluorophenyl)sulfonyl)piperidine-1-carboxylate (32.7 mg, 0.095mmol) in dioxane (238 μL) at room temperature was treated with HCl (4 Min dioxane, 190 μL, 0.762 mmol) and the resulting reaction mixture wasstirred for 4 h. The solvent was removed to give the title compound asits HCl salt (25 mg, 94%) as a white solid. ESI-MS m/z [M+H]⁺ 243.95.

Preparation 13 1-(2,4-difluorobenzyl)piperazine

A mixture of piperazine (26.5 g, 308 mmol) in THF (350 mL) was heated to70° C. and 1-(chloromethyl)-2,4-difluorobenzene (5 g, 30.8 mmol) wasadded. The suspension was heated at 70° C. overnight. The solid(piperazine) was filtered off, and the solvent was removed under reducedpressure. The residue was partitioned between EtOAc and water. Theorganic layer was dried and concentrated to give the title compound (6g, 92%). ESI-MS m/z [M+H]⁺ 213.04.

Preparation 14 4-(2-fluoro-4-methoxyphenoxy)piperidine

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g,12.03 mmol) in THF (33.4 mL) at room temperature was treated with2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine(3.16 g, 12.03 mmol). The reaction mixture was cooled to 0° C. and DEAD(40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise viasyringe. The resulting reaction mixture was stirred at 65° C. for 5 h,then at room temperature overnight. Flash silica gel chromatographyusing a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 85%) as alight yellow oil. ESI-MS m/z [M+Na]⁺ 348.2.

A solution of tert-butyl4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 8.54mmol) in dioxane (21.36 mL) was treated with HCl (4 M in dioxane, 21.36mL, 85 mmol) at room temperature and the resulting reaction mixturestirred overnight. Flash silica gel chromatography using a gradient of5% to 30% MeOH in DCM gave the title compound as its HCl salt (1.7 g,76%) as a white solid. ESI-MS m/z [M+H]⁺ 226.20.

Preparation 153-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine

A solution of 2,3-dichloropyrido[3,4-b]pyrazine (492 mg, 2.460 mmol) inDCM (5 mL) at 0° C. was treated with 4-(2,4-difluorophenoxy)piperidinehydrochloride (676 mg, 2.71 mmol) and DIPEA (1.29 mL, 7.38 mmol). Thereaction mixture was allowed to stir overnight, gradually warming toroom temperature. The reaction mixture was quenched with the addition ofsaturated aqueous NH₄Cl and was extracted with DCM. The organic layerwas dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash silica gel chromatographyusing a gradient of 20% to 60% EtOAc in heptanes to give the titlecompound as a pale yellow solid (736.2 mg, 79%). ESI-MS m/z [M+H]⁺377.4.

Preparation 164-((1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile

To a solution of 2,3-dichloropyrido[3,4-b]pyrazine (1.00 g, 5.00 mmol)in DCM (10.0 mL) at 0° C. was added DIPEA (2.62 mL, 15.00 mmol) and3-fluoro-4-(piperidin-4-yloxy)benzonitrile hydrochloride (1.283 g, 5.00mmol). The reaction mixture was stirred for 30 min, warming gradually toroom temperature. The reaction mixture was treated with saturatedaqueous NH₄Cl. The organic layer containing yellow solid was collectedand concentrated under reduced pressure. The solid was filtered, washingwith water, and was lyophilized overnight to give the title compound asa yellow solid (1.325 g, 69%). ESI-MS m/z [M+H]⁺ 384.3.

Preparation 17(R)-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to Preparation 18using (R)-4-((2,4-difluorophenyl)fluoromethyl)piperidine hydrochloridein place of 4-(2,4-difluorophenoxy)piperidine hydrochloride. ESI-MS m/z[M+H]⁺ 393.4.

Preparation 19(S)-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to Preparation 20using (S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine hydrochloridein place of 4-(2,4-difluorophenoxy)piperidine hydrochloride. ESI-MS m/z[M+H]⁺ 393.4.

Preparation 213-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine

To a mixture of 2,3-dichloropyrido[3,4-b]pyrazine (8 g, 40.0 mmol)and1-(2,4-difluorobenzyl)piperazine (8.49 g, 40.0 mmol) in DCM (100 mL) wasadded triethylamine (16.72 mL, 120 mmol) at room temperature. Then themixture was stirred at room temperature for 0.5 h. The reaction mixturewas diluted with 30 mL of DCM, washed with brine twice, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography, eluting with a gradient of 50:1 to 5:1 PE:EtOAc togive the title compound (12 g, 80%). ESI-MS m/z [M+H]⁺ 376.0.

Preparation 223-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine

A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (144mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol)and DIPEA (260 μL, 1.500 mmol) in DCM (1.0 mL) was stirred at roomtemperature for 30 min. The mixture was then partitioned between EtOAcand saturated aqueous NH₄Cl. The organic layer was washed with brine,dried over Na₂SO₄, filtered and evaporated. The residue was dissolved inEtOAc and filtered through a silica pad. The filtrate was concentratedto afford the crude title compound (200.7 mg, 100%) as a yellow oil,which was used without further purification. ESI-MS m/z [M+H]⁺ 389.2.

Preparation 23 tert-butyl4-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate

Combine 2,3-dichloropyrido[3,4-b]pyrazine (2.0 g, 10.00 mmol),tert-butyl piperazine-1-carboxylate (1.955 g, 10.50 mmol) and DCM (25mL) to furnish a yellow-orange suspension. Next, DIPEA (5.22 mL, 30.0mmol) was added to the flask over 1 min at 0° C. The mixture was stirredat 0° C. for 2 h under nitrogen, warmed slowly to 23° C., and stirredfor 17 h. The reaction mixture was partitioned between saturated aqueousNH₄Cl (20 mL) and EtOAc (80 mL) to furnish two layers. The layers wereseparated, and the aqueous phase was washed with EtOAc (80 mL). Theorganic extracts were combined, washed with brine (10 mL), dried overNa₂SO₄, filtered, rinsed with EtOAc, and dried in vacuo to give thetitle compound (3.35 g, 96%) as an orange semisolid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.44 (s, 9H), 3.51-3.58 (m, 4H), 3.62-3.68 (m, 4H), 7.67(d, J=1.0 Hz, 1H), 8.66 (d, J=5.9 Hz, 1H), 9.15 (d, J=1.0 Hz, 1H);ESI-MS m/z [M+H]⁺ 350.5.

Preparation 24 tert-butyl4-(3-(isopropylamino)pyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate

To a flask charged with tert-butyl4-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate (3.35 g,9.58 mmol) and potassium fluoride (0.723 g, 12.45 mmol) in DMSO (25 mL)was added DIPEA (3.34 mL, 19.15 mmol) and propan-2-amine (2.468 mL, 28.7mmol) at 23° C. The reaction was stirred at 23° C. for 22 hr and dilutedwith water (100 mL) to furnish an orange, oily sludge. The mixture wascooled to 0° C. to furnish a yellow-orange suspension. The resultingsolid was filtered, rinsed with water, and dried in vacuo. The crudematerial was dissolved in EtOAc, adsorbed on NH silica gel (11 g), andpurified via medium pressure chromatography using a gradient of 10% to100% EtOAc in heptane on an NH 60 μM size 400 column (Shoko ScientificPurif-Pack™) to give the title compound (2.105 g, 59.0%) as a lightyellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.26 (d, J=6.8 Hz, 6H),1.43 (s, 9H), 3.30-3.33 (m, 4H), 3.52-3.60 (m, 4H), 4.32-4.42 (m, 1H),6.54 (d, J=7.8 Hz, 1H), 7.43-7.46 (m, 1H), 8.29 (d, J=5.4 Hz, 1H), 8.78(s, 1H); ESI-MS m/z [M+H]⁺ 373.0.

Preparation 25(1s,3s)-3-((2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-yl)amino)cyclobutan-1-ol

Combined3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine(0.75 g, 1.996 mmol), (1s,3s)-3-aminocyclobutanol hydrochloride (0.740g, 5.99 mmol), and potassium fluoride (0.151 g, 2.59 mmol) in DMSO (7.5mL) and added DIPEA (1.738 mL, 9.98 mmol) at 23° C. The reaction mixturewas stirred at 23° C. for 5 days and diluted with water (30 mL) tofurnish a yellow-orange suspension. The resulting solid was filtered,rinsed with water, and dried in vacuo to give the title compound (690mg, 81%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.92-2.02 (m, 2H), 2.61-2.70 (m, 6H),3.38 (br s, 4H), 3.60 (s, 2H), 3.90-3.98 (m, 1H), 3.99-4.07 (m, 1H),5.08 (d, J=5.9 Hz, 1H), 6.93-6.98 (m, 1H), 7.09 (td, J=8.4, 2.7 Hz, 1H),7.20-7.25 (m, 1H), 7.41-7.45 (m, 1H), 7.47-7.53 (m, 1H), 8.28 (d, J=5.9Hz, 1H), 8.75 (s, 1H); ESI-MS m/z [M+H]⁺ 427.0.

Preparation 26(1s,3s)-3-((2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-yl)amino)cyclobutan-1-ol

Combined3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(0.75 g, 1.991 mmol), (1s,3s)-3-aminocyclobutanol hydrochloride (0.738g, 5.97 mmol), and potassium fluoride (0.150 g, 2.59 mmol) in DMSO (7.5mL) and added DIPEA (1.734 mL, 9.95 mmol) at 23° C. The reaction mixturewas stirred at 23° C. for 5 days and diluted with water (30 mL) tofurnish a yellow-orange suspension. The resulting solid was filtered,rinsed with water, and dried in vacuo to give the title compound (784mg, 92%) as a yellow-orange solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.87-2.03 (m, 4H), 2.07-2.18 (m, 2H), 2.61-2.73 (m, 2H), 3.19-3.29 (m,2H), 3.63-3.73 (m, 2H), 3.89-3.99 (m, 1H), 3.99-4.10 (m, 1H), 4.62 (tt,J=7.9, 3.8 Hz, 1H), 5.08 (d, J=5.9 Hz, 1H), 6.99-7.10 (m, 2H), 7.26-7.38(m, 2H), 7.44 (d, J=5.4 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 8.76 (s, 1H);ESI-MS m/z [M+H]⁺ 427.9.

Preparation 27(1r,3r)-3-((2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-yl)amino)cyclobutan-1-ol

Combined3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(0.75 g, 1.991 mmol), (1r,3r)-3-aminocyclobutanol hydrochloride (0.738g, 5.97 mmol), and potassium fluoride (0.150 g, 2.59 mmol) in DMSO (7.5mL) and added DIPEA (1.734 mL, 9.95 mmol) at 23° C. The reaction wasstirred at 23° C. for 5 days and diluted with water (30 mL) to furnish agummy, brown suspension. The suspension was cooled on ice, stirred for30 min at 0° C., filtered, rinsed with water, and the resulting solidwas dried in vacuo to give the title compound (802 mg, 94%) as a lightbrown solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.86-1.96 (m, 2H),2.07-2.15 (m, 2H), 2.23 (ddd, J=12.6, 7.9, 4.4 Hz, 2H), 2.33-2.40 (m,2H), 3.23-3.30 (m, 2H), 3.67-3.74 (m, 2H), 4.30-4.37 (m, 1H), 4.56-4.65(m, 2H), 5.03 (d, J=4.9 Hz, 1H), 7.00-7.07 (m, 2H), 7.29-7.37 (m, 2H),7.44 (d, J=4.9 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 8.77 (s, 1H); ESI-MS m/z[M+H]⁺ 427.9.

Preparation 28N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine

To a solution of3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(10 g, 26.5 mmol) in DMF (150 mL) was added cyclobutanamine (15.10 g,212 mmol) at rt. Then the mixture was stirred at 70° C. for 15 h. Afterthe reaction was done, the reaction mixture was poured into water/ACN(200 mL, 7:3). The suspension was filtered and rinsed with ACN to givethe title compound (8.5 g, 78%). ESI-MS m/z [M+H]⁺ 412.1.

Preparation 28N-(3,3-difluorocyclobutyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine

Combined3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(0.46 g, 1.221 mmol), 3,3-difluorocyclobutanamine hydrochloride (0.526g, 3.66 mmol), and potassium fluoride (0.092 g, 1.587 mmol) in DMSO (5mL) and added DIPEA (1.063 mL, 6.10 mmol) at 23° C. The reaction wasstirred at 23° C. for 5 days and diluted with water (20 mL) to furnish ayellow-orange suspension. The resulting solid was filtered, rinsed withwater, and dried in vacuo to give the title compound (516.4 mg, 95%) asa yellow-orange solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.87-1.98 (m,2H), 2.07-2.18 (m, 2H), 2.77-2.91 (m, 2H), 2.96-3.07 (m, 2H), 3.23-3.32(m, 2H), 3.69-3.78 (m, 2H), 4.35-4.45 (m, 1H), 4.63 (tt, J=7.9, 3.8 Hz,1H), 7.00-7.07 (m, 1H), 7.24-7.40 (m, 3H), 7.48 (d, J=5.4 Hz, 1H), 8.33(d, J=5.4 Hz, 1H), 8.82 (s, 1H); ESI-MS m/z [M+H]⁺ 447.9.

Preparation 302-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine

A solution of3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(2 g, 5.31 mmol), propan-2-amine (1.36 mL, 15.92 mmol) and DIPEA (1.85mL, 10.62 mmol) in dioxane (10.62 mL) was heated at 95° C. overnight.After concentration, the residue was purified with silica gel columnchromatography using a gradient of 0% to 100% EtOAc in heptanes to givethe title compound (1.5 g, 71%) as an off-white solid. ESI-MS m/z [M+H]⁺400.00.

Preparation 31 9(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

To a mixture of3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(2.5 g, 6.64 mmol) in DMF (30 mL) was added (S)-tetrahydrofuran-3-aminehydrochloride (4.10 g, 33.2 mmol) and Et₃N (9.25 mL, 66.4 mmol) at roomtemperature. The reaction mixture was stirred at 70° C. for 14 h thencooled to room temperature and diluted with EtOAc (80 mL), washed withwater (30 mL) and brine (2×30 mL). The organic layer was dried overNa₂SO₄ and concentrated in vacuo, then the residue was purified bycolumn chromatography (petroleum ether:EtOAc from 10:1 to 1:1) on silicagel to give the title compound as a yellow solid (2.0 g). ESI-MS m/z[M+H]⁺ 428.1.

Preparation 32(R)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

To a mixture of3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine(5.06 g, 13.46 mmol) in DMSO (40 mL) was added(R)-tetrahydrofuran-3-amine hydrochloride (4.16 g, 33.7 mmol) and Et₃N(24.40 mL, 175 mmol) at room temperature. The reaction mixture wasstirred at 50° C. for 14 h then cooled to room temperature and dilutedwith EtOAc (80 mL), washed with water (30 mL) and brine (2×30 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo, then theresidue was purified by column chromatography (petroleum ether:EtOAcfrom 10:1 to 1:1) on silica gel to give the title compound as a yellowsolid (5.0 g). ESI-MS m/z [M+H]⁺ 427.1.

Preparation 33(S)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

To a solution of3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine(3.0 g, 7.98 mmol) and Et₃N (10 mL, 71.7 mmol) in DMF (30 mL) was added(S)-tetrahydrofuran-3-amine hydrochloride (2.96 g, 23.95 mmol) at roomtemperature. The mixture was stirred at 60° C. for 16 h then separatedbetween water and EtOAc. The organic layer was washed with brine andwater, then dried and concentrated to yield the crude residue, which waspurified by column to give the title compound (800 mg) as a yellow oil.ESI-MS m/z [M+H]⁺ 427.1.

Preparation 342-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine

To a flask charged with3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine(2.34 g, 6.23 mmol) and potassium fluoride (0.470 g, 8.09 mmol) in DMSO(12 mL) was added DIPEA (2.169 mL, 12.45 mmol) and propan-2-amine (1.605mL, 18.68 mmol) at 23° C. The reaction was stirred at 23° C. for 22 hrand diluted with water (48 mL) to furnish an orange, oily sludge. Thecrude product was extracted with EtOAc (25 mL) to furnish a suspension.The resulting solid was filtered, rinsed with EtOAc, and the filtratewas allowed to separate into two layers. The organic phase was washedwith brine, dried over Na₂SO₄, filtered, rinsed with EtOAc, and dried invacuo. The crude material was dissolved in toluene (5 mL) and purifiedvia medium pressure chromatography using a 20% to 100% gradient eluantof EtOAc in heptane on an NH 60 μM, size 400 column (Shoko ScientificPurif-Pack™) to give the title compound (1.489 g, 60.0%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.24 (d, J=6.4 Hz, 6H), 2.62 (t,J=4.9 Hz, 4H), 3.34-3.41 (m, 4H), 3.59 (s, 2H), 4.22-4.42 (m, 1H), 6.46(d, J=7.8 Hz, 1H), 7.04-7.17 (m, 1H), 7.22 (td, J=10.0, 2.4 Hz, 1H),7.40-7.44 (m, 1H), 7.49 (td, J=8.5, 6.8 Hz, 1H), 8.27 (d, J=5.9 Hz, 1H),8.76 (s, 1H); ESI-MS m/z [M+H]⁺ 399.0.

Preparation 35N-cyclobutyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine

Combined3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine(0.7226 g, 1.923 mmol), cyclobutanamine (0.493 mL, 5.77 mmol), andpotassium fluoride (0.145 g, 2.500 mmol) in DMSO (7.2 mL) and DIPEA(0.670 mL, 3.85 mmol) at 23° C. The reaction was stirred at 23° C. for16 hr and diluted with water (30 mL) to furnish a yellow-orangesuspension. The resulting solid was filtered, rinsed with water, anddried in vacuo to give the title compound (0.62 g, 79%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.68-1.77 (m, 2H), 2.12 (quind,J=9.3, 2.7 Hz, 2H), 2.27-2.35 (m, 2H), 2.56-2.68 (m, 4H), 3.35-3.42 (m,4H), 3.60 (s, 2H), 4.57 (sextet, J=8.0 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H),7.06-7.12 (m, 1H), 7.22 (td, J=9.9, 2.7 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H),7.46-7.53 (m, 1H), 8.27 (d, J=5.4 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z[M+H]⁺ 411.0.

Preparation 366-benzyl-3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

A mixture of3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(93 mg, 0.239 mmol) and (bromomethyl)benzene (29 μL, 0.239 mmol) in ACN(1.2 mL) was heated at 80° C. for 14 h. After the mixture was cooled toroom temperature, sodium triacetoxyborohydride (152 mg, 0.718 mmol) wasadded to the mixture at rt. After 1 h, brine (1 mL) was added to themixture. After bubbling ceased, the mixture was then purified directlyby HPLC Method A to give the title compound as a TFA salt (71.2 mg,49.9%) as a yellow oil. ESI-MS m/z [M+H]⁺ 483.3.

Preparation 373-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

The title compound as a TFA salt (30.9 mg, 24.8%) was prepared in amanner similar to Preparation 38 using iodomethane. ESI-MS m/z [M+H]⁺407.3.

Preparation 396-benzyl-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

A mixture of 4-((2,4-difluorophenyl)fluoromethyl)piperidinehydrochloride (247 mg, 0.929 mmol), 2,3-dichloropyrido[3,4-b]pyrazine(169 mg, 0.845 mmol) and DIPEA (441 μL, 2.53 mmol) in DCM (1.69 mL) wasstirred at 0° C. for 5 min then at rt for 30 min. The mixture was thenpartitioned between EtOAc and saturated aqueous NH₄Cl. The organic layerwas washed with brine, dried over Na₂SO₄, filtrered, and evaporated. Theresidue was dissolved in EtOAc and filtered through a pad of silica. Thefiltrate was concentrated to afford3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine(338.4 mg) as a yellow foam. ESI-MS m/z [M+H]⁺ 393.2.

A mixture of3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine(338.4 mg, 0.861 mmol) benzyl bromide (103μL, 0.861 mmol) in ACN (4.31mL) was heated at 80° C. for 14 h. After the mixture was cooled to rt,sodium triacetoxyborohydride (548 mg, 2.58 mmol) was added. After 1 h,brine (1 mL) was added to the mixture. After bubbling ceased, themixture was then purified directly by HPLC Method A to afford the titlecompound as its TFA salt (141.7 mg, 27.4%) as an orange oil. ESI-MS m/z[M+H]⁺ 487.3.

Preparation 406-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

Combined 2,3-dichloro-5-methylpyrido[3,4-b]pyrazine (1 g, 4.67 mmol),DIPEA (2.04 mL, 11.68 mmol), and 4-(2,4-difluorophenoxy)piperidinehydrochloride (1.225 g, 4.91 mmol) in DCM (9.34 mL) were combined in anice bath then warmed to room temperature overnight. The reaction mixturewas poured into 1 M NaOH, extracted with EtOAc (2×), filtered throughMgSO₄, concentrated in vacuo, and purified by HPLC Method A to give3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazineas a TFA salt (1.6 g).

Combined3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazine(400 mg, 1.024 mmol) and benzyl bromide (122 μL, 1.024 mmol) in ACN(5.12 mL) was heated at 90° C. overnight. The reaction mixture wascooled to RT, sodium triacetoxyborohydride was added (651 mg, 3.07mmol), and the reaction mixture was stirred overnight. The crudereaction was poured into 1 M NaOH, extracted with EtOAc (2×), filteredthrough MgSO₄, concentrated in vacuo, and purified by HPLC Method A toyield the title compound as a TFA salt (150 mg).

Preparation 416-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

Benzyl bromide was purified by passage through a plug of basic aluminaprior to use. A solution of3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine(736.2 mg, 1.954 mmol) in ACN (9.77 mL) was divided into two equalportions. Each solution was treated with a half portion of benzylbromide (232 μL, 1.954 mmol) and stirred at 80° C. for 3 h. The reactionmixtures were allowed to cool to room temperature, and Each solution wastreated with a half portion of sodium triacetoxyborohydride (1.242 g,5.86 mmol). The reaction mixtures were stirred at room temperature for 1h, then were quenched with saturated aqueous NaCl. The reaction mixtureswere combined and partitioned between EtOAc with Et₂O added to assist inphase separation and saturated aqueous NaCl. The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash silica gel chromatography using a 20% to60% gradient of EtOAc in heptanes gave the title compound (522.2 mg,56.8%). ESI-MS m/z [M+H]⁺ 471.4.

Preparation 424-((1-(6-benzyl-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile

Benzyl bromide was purified by filtration through a plug of basicalumina prior to use. A solution of4-((1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile(200 mg, 0.521 mmol) and benzyl bromide (0.062 mL, 0.521 mmol) in ACN(2.60 mL) was heated at 80° C. for 3 h. The reaction mixture was allowedto cool to room temperature and sodium triacetoxyborohydride (331 mg,1.563 mmol) was added. After stirring for 1 h at room temperature, thereaction mixture was quenched with saturated aqueous NaCl (1 mL). Afterbubbling ceased, the reaction mixture was purified by HPLC Method B,with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm columnwas used, using a 35% to 70% ACN gradient to give the title compound, asa TFA salt, as a yellow oil (117.9 mg, 38.2%). ESI-MS m/z [M+H]⁺ 478.5.

Preparation 43(R)-6-benzyl-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to Preparation 44using(R)-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine.The product was purified twice by flash silica gel chromatography usinga 10% to 60% gradient of EtOAc in heptanes. ESI-MS m/z [M+H]⁺ 487.4.

Preparation 45(S)-6-benzyl-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to Preparation 46using(S)-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine.The product was purified twice by flash silica gel chromatography usinga 10% to 50% gradient of EtOAc in heptanes. ESI-MS m/z [M+H]⁺ 487.3.

Preparation 476-benzyl-N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution of6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine(261.1 mg, 0.554 mmol) and 2,2-difluoroethanamine (156 μL, 2.22 mmol) intoluene (1.85 mL) was treated with sodium tert-butoxide (107 mg, 1.11mmol), BINAP (69.0 mg, 0.111 mmol), and Pd₂(dba)₃ (50.8 mg, 0.055 mmol).Nitrogen gas (balloon) was bubbled through the reaction mixture for 5min. The reaction mixture was sealed and stirred at 90° C. overnight.The reaction mixture was allowed to cool to room temperature and wasopened to air, and the solution was concentrated under reduced pressure.The residue was taken up in MeOH, filtered, and purified by HPLC MethodB using a 35% to 60% ACN gradient to give the title compound, as a TFAsalt, as a yellow oil (181.2 mg, 51.9%). ESI-MS m/z [M+H]⁺ 516.4.

Preparation 486-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

To a yellow-orange suspension of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine(5.1 g, 12.77 mmol) in ACN (63.8 mL) was added benzyl bromide (2.184 g,12.77 mmol) over 1 minute at 23° C. The mixture was stirred at 80° C.for 4 h to furnish a red-brown solution, cooled to 23° C., and thenconcentrated via rotary evaporation to give6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)pyrido[3,4-b]pyrazin-6-iumbromide (7.30 g) as a red-brown solid, which was used directly in thenext step without further purification.

To a solution of6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)pyrido[3,4-b]pyrazin-6-iumbromide (7.2 g, 12.62 mmol) in DCM (126 ml) was added NaBH(OAc)₃ (16.05g, 76 mmol).The resulting solution was stirred at room temperature for 3days. After DCM was removed under vacuum, EtOAc (200 mL) was added tore-dissolve the residue. Then saturated NaHCO₃ (150 mL) was added andthe mixture was vigorously stirred for 30 min. The organic layer waswashed with water (50 mL) and brine (50 mL), and dried with anhydrousNa₂SO₄ overnight. Removal of the solvent gave the title compound (6.43g) as a yellow solid, which was used without further purification.ESI-MS m/z [M+H]⁺ 494.10.

Preparation 506-benzyl-N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 51 using cyclobutanamine in place of 2,2-difluoroethanamineand HPLC Method A. ESI-MS m/z [M+H]⁺ 506.00.

Preparation 52(S)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 53 using (S)-1-methoxypropan-2-amine in place of2,2-difluoroethanamine and HPLC Method A. ESI-MS m/z [M+H]⁺ 524.00.

Preparation 54(R)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 55 using (R)-1-methoxypropan-2-amine hydrochloride in placeof 2,2-difluoroethanamine and HPLC Method A. ESI-MS m/z [M+H]⁺ 524.00.

Preparation 56(S)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 57 using (S)-butan-2-amine in place of2,2-difluoroethanamine and HPLC Method A. ESI-MS m/z [M+H]⁺ 508.00.

Preparation 58(R)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 59 using (R)-butan-2-amine in place of2,2-difluoroethanamine and HPLC Method A. ESI-MS m/z [M+H]⁺ 508.00.

Preparation 604-((1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile

A solution of4-((1-(6-benzyl-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrileTFA salt (213.9 mg, 0.361 mmol) in toluene (1.44 mL) was treated withpropan-2-amine (0.118 mL, 1.445 mmol), sodium tert-butoxide (69.4 mg,0.723 mmol), BINAP (22.5 mg, 0.036 mmol), and Pd₂(dba)₃ (16.5 mg, 0.018mmol). Nitrogen gas was bubbled through the solution for 5 min. Thereaction mixture was then sealed and the reaction mixture was heated to90° C. overnight. The reaction mixture was allowed to cool to roomtemperature. Solvent was removed under reduced pressure and the residuewas purified by HPLC Method B, with the exception that a Waters SunFire™C18, 5 μm, ID 30×75 mm column was used, using a 40% to 70% ACN gradientto give the title compound, as a TFA salt, as a yellow oil (105 mg,47.3%). ESI-MS m/z [M+H]⁺ 501.5.

Preparation 61(R)-6-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution of(R)-6-benzyl-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine(293 mg, 0.602 mmol) and propan-2-amine (197 μL, 2.407 mmol) in toluene(2.01 mL) was treated with sodium tert-butoxide (116 mg, 1.203 mmol),BINAP (74.9 mg, 0.120 mmol), and Pd₂(dba)₃ (55.1 mg, 0.060 mmol).Nitrogen gas (balloon) was bubbled through the reaction mixture for 5min. The reaction mixture was sealed and the reaction mixture wasstirred at 90° C. overnight. The reaction was opened and the mixture wasconcentrated under reduced pressure. The residue was taken up in MeOH,filtered, and purified by HPLC Method B using a 40% to 65% ACN gradientto give the title compound as a TFA salt (183.1 mg, 48.8%) as a yellowoil. ESI-MS m/z [M+H]⁺ 510.4.

Preparation 62(S)-6-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution of(S)-6-benzyl-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine(500 mg, 1.027 mmol) and propan-2-amine (350 μL, 4.11 mmol) in toluene(3.42 mL) was treated with sodium tert-butoxide (197 mg, 2.054 mmol),BINAP (102 mg, 0.164 mmol), and Pd₂(dba)₃ (75 mg, 0.082 mmol). Nitrogengas (balloon) was bubbled through the reaction mixture for 5 min. Thereaction mixture was then sealed and heated at 90° C. for 16 h. Thereaction mixture was allowed to cool to room temperature and was openedto air. The reaction mixture was concentrated under reduced pressure andwas taken up in MeOH, filtered, and purified by HPLC Method A to givethe title compound as a TFA salt (266 mg) as an orange oil. ESI-MS m/z[M+H]⁺ 510.4.

Preparation 633-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile

To a solution of4-((1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrileTFA salt (98.8 mg, 0.161 mmol) in THF (1.61 mL) was added Pd(OH)₂ (20 wt%, 33.9 mg, 0.048 mmol). Hydrogen gas (balloon) was bubbled through thereaction mixture for 5 min. The reaction mixture was allowed to stirunder hydrogen atmosphere for 6 h. The reaction mixture was filteredthrough a plug of Celite™, eluting with MeOH. The filtrate was collectedand concentrated under reduced pressure. The residue was purified byHPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID30×75 mm column was used, using a 25% to 60% ACN gradient to give thetitle compound, as a TFA salt, as a yellow oil (12.8 mg), which wascarried forward without additional purification. ESI-MS m/z [M+H]⁺411.5.

Preparation 64N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution of6-benzyl-N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (132.5 mg, 0.210 mmol) in THF (2.1 mL) was treated with Pd(OH)₂(20 wt %, 29.6 mg, 0.042 mmol). Hydrogen gas (balloon) was bubbledthrough the reaction mixture for 5 min. The vent needle was removed andthe reaction was stirred under hydrogen atmosphere for 1 h. The reactionmixture was opened to air and was filtered through a pad of Celite™,eluting with EtOAc and MeOH. The filtrate was concentrated under reducedpressure to give the title compound as a TFA salt (114 mg), which wasused without further purification. ESI-MS m/z [M+H]⁺ 426.5.

Preparation 65N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 66, except that the reaction was stirred under hydrogenatmosphere for 2 h. ESI-MS m/z [M+H]⁺ 416.5.

Preparation 67(R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 68, except that the reaction was stirred under hydrogenatmosphere for 2 h. The TFA salt was dissolved in DCM and washed withsaturated aqueous K₂CO₃. The organics were dried over Na₂SO₄, filtered,and concentrated under reduced pressure to obtain the title compound asthe free base. ESI-MS m/z [M+H]⁺ 420.5.

Preparation 69(S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound as a TFA salt was prepared in a manner similar toPreparation 70. The TFA salt was dissolved in DCM and washed withsaturated aqueous K₂CO₃. The organics were dried over Na₂SO₄, filtered,and concentrated under reduced pressure to obtain the title compound asthe free base. ESI-MS m/z [M+H]⁺ 420.5.

Preparation 71N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of cyclobutanamine (49.9 μL, 0.584 mmol),6-benzyl-3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazineTFA salt (116.2 mg, 0.195 mmol), sodium tert-butoxide (56.1 mg, 0.584mmol), BINAP (18.2 mg, 0.029 mmol) and Pd₂(dba)₃ (26.7 mg, 0.029 mmol)in toluene (649 μL) was heated at 90° C. in a sealed tube for 16 h. Themixture was directly purified by HPLC Method A to afford6-benzyl-N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineas its TFA salt (103.4 mg, 84%) as a yellow foam. ESI-MS m/z [M+H]⁺518.4

A mixture of6-benzyl-N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (103.4 mg, 0.164 mmol) and Pd(OH)₂ on carbon (10 mg, 0.014mmol) in THF (818 μL) was stirred at rt under an atmosphere of hydrogengas (balloon) for 4 h. The mixture was filtered through a pad ofCelite™, washing with MeOH, and concentrated to afford the titlecompound as its TFA salt (89 mg, 100%) as a yellow solid. ESI-MS m/z[M+H]⁺ 428.4.

Preparation 721-(3-(isopropylamino)-2-(piperazin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To a flask charged with tert-butyl4-(6-acetyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate(1.015 g, 2.425 mmol) was added HCl (4 M in dioxane, 4.85 mL, 19.40mmol) at 23° C. The reaction mixture was stirred at 23° C. for 1 h,diluted with dioxane (20 mL), filtered, rinsed with dioxane, and driedin vacuo to provide the HCl salt of the title compound (0.861 g, 100%)as a yellow solid. ESI-MS m/z [M+H]⁺ 319.5.

Preparation 732-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

Combined6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazineTFA salt (280 mg, 0.467 mmol), isopropylamine (200 μL, 2.337 mmol),Pd₂(dba)₃ (42.8 mg, 0.047 mmol), BINAP (58.2 mg, 0.093 mmol), and sodiumtert-butoxide (112 mg, 1.169 mmol) in toluene (2.34 mL) and heated at100° C. for 30 min under microwave conditions. The reaction mixture wascooled, concentrated in vacuo, and purified by HPLC Method A to give6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineas a TFA salt (175 mg) as a brown oil.

A 50 mL round-bottomed flask containing6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (175 mg, 0.282 mmol) and Pd(OH)₂ (20 wt %, 39.5 mg, 0.056 mmol)in THF (2.82 mL) was purged and placed under hydrogen (balloon) for 3 h.Filtration through Celite™ (washed with EtOAc) and concentration invacuo gave the title compound as a TFA salt (150 mg) as a brown oil.

Preparation 74N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound (98 mg) was prepared in a manner similar toPreparation 75 using 2,2-difluoroethan-1-amine.

Preparation 76(5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone

A mixture of (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanonehydrochloride (153 mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine(100 mg, 0.500 mmol) and DIPEA (261 μL, 1.500 mmol) in DCM (1.67 mL) wasstirred at rt for 30 min. The mixture was partitioned between aqueousNH₄Cl and EtOAc. The organic layer was filtered through a pad of silica,washing with EtOAc, and the filtrate was concentrated under reducedpressure to give(5-chloro-2-fluorophenyl)(1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone(205.5 mg) as an orange solid. ESI-MS m/z [M+H]⁺ 405.2.

A mixture of(5-chloro-2-fluorophenyl)(1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone(205.5 mg, 0.507 mmol) and benzyl bromide (63.7 μL, 0.532 mmol) in ACN(1.69 mL) was heated at 80° C. for 4 h. After the mixture was cooled tort, sodium triacetoxyborohydride (537 mg, 2.54 mmol) was added in oneportion. After 1 h, the mixture was quenched with brine, extracted withEtOAc, concentrated and purified by HPLC Method A to afford(1-(6-benzyl-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanoneas its TFA salt (112.4 mg, 36.1%) as a yellow oil. ESI-MS m/z [M+H]⁺499.2.

A mixture of propan-2-amine (31.5 μL, 0.366 mmol),(1-(6-benzyl-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanoneTFA salt (112.4 mg, 0.183 mmol), sodium tert-butoxide (35.2 mg, 0.366mmol), BINAP (17.1 mg, 0.027 mmol) and Pd₂(dba)₃ (8.4 mg, 9.16 μmol) intoluene (611 μL) was heated at 100° C. for 16 h. The mixture waspurified by HPLC Method A to afford(1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanoneas its TFA salt (41.7 mg, 35.8%) as a yellow film. ESI-MS m/z [M+H]⁺522.4.

A mixture of(1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanoneTFA salt (41.7 mg, 0.066 mmol) and Pd(OH)₂ on carbon (20 wt %, 5 mg,0.036 mmol) in THF (328 μL) was stirred at rt under an atmosphere ofhydrogen gas (balloon). After 3 h, the mixture was diluted with MeOH,filtered through a pad of Celite™, washing with MeOH, and concentratedto afford the title compound as its TFA salt (36 mg, 100%) as a yellowfilm, which was used without further purification. ESI-MS m/z [M+H]⁺432.3.

Preparation 77 3-chloro-N-isopropylpyrido[3,4-b]pyrazin-2-amine

To a solution of 2,3-dichloropyrido[3,4-b]pyrazine (2.5 g, 12.50 mmol)and DIPEA (6.53 mL, 37.5 mmol) in DCM (25 mL) was added propan-2-amine(1.065 mL, 12.50 mmol) at 0° C. The mixture was stirred at 0° C. for 30min, warmed slowly to 23° C., and stirred for 12 h. The crude mixturewas partitioned between EtOAc (100 mL) and saturated aqueous NH₄Cl (100mL). The layers were separated and the aqueous phase was washed withEtOAc (4×100 mL). The organic extracts were combined, washed with brine(50 mL), dried over Na₂SO₄, filtered, rinsed with EtOAc, and dried invacuo. The crude material was dissolved in toluene (5 mL) and purifiedvia medium pressure chromatography using a gradient eluant of 50% to 75%EtOAc in heptane on a 80 g silica gel column (Single Step™) to give thetitle compound (1.828 g, 65.7%) as a yellow-orange solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.28 (d, J=6.6 Hz, 6H), 4.39-4.49 (m, 1H), 7.49 (dd,J=5.8, 0.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.95(d, J=0.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 223.1.

Preparation 78 3-chloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine

A solution of 2,3-dichloropyrido[3,4-b]pyrazine (3.55 g, 17.75 mmol) indioxane (71.0 mL) at room temperature was treated with cyclopropanamine(1.63 mL, 23.07 mmol), followed by dropwise addition of DIPEA (6.51 mL,37.3 mmol). The resulting reaction mixture was stirred at roomtemperature for 12 h. Purification by flash silica gel chromatographyusing a gradient of 25% to 100% EtOAc in hexanes gave the title compound(3.15 g, 80%) as an orange solid. ESI-MS m/z [M+H]⁺ 221.1.

Preparation 793-chloro-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-2-amine

A solution of 2,3-dichloropyrido[3,4-b]pyrazine (50 mg, 0.250 mmol) indioxane (250 μL) was treated with 2,2-difluoroethanamine (21.0 μL, 0.275mmol) and DIPEA (131 μL, 0.750 mmol). The resulting reaction mixture wasstirred at 70° C. for 1 h then purified by flash silica gelchromatography using a gradient of 0% to 60% EtOAc in hexanes to givethe title compound (52 mg, 85%) as a light yellow solid.

Preparation 806-benzyl-3-chloro-N-cyclopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 3-chloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine (301.8mg, 1.368 mmol) and (bromomethyl)benzene (170 μL, 1.436 mmol) in ACN(4.5 mL) was heated at 80° C. for 3 h. Sodium triacetoxyborohydride(1449 mg, 6.8 mmol) was added to the mixture at rt. After 30 min, brinewas added to the mixture. After stirring for 1 h, the layers wereseparated and the organic layer was purified by HPLC Method A to givethe title compound as a TFA salt (290.6 mg, 49.5%) as a yellow solid.ESI-MS m/z [M+H]⁺ 315.2.

Preparation 813-chloro-N-cyclopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

The title compound as a TFA salt (22 mg, 17.2%) was prepared in a mannersimilar to Preparation 82 using iodomethane. ESI-MS m/z [M+H]⁺ 239.2.

Preparation 836-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

The title compound as a TFA salt (240 mg, 41.3%) was prepared in amanner similar to Preparation 84 using3-chloro-N-isopropylpyrido[3,4-b]pyrazin-2-amine. ESI-MS m/z [M+H]⁺317.3.

Preparation 856-benzyl-3-chloro-N-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution of 3-chloro-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-2-amine(200 mg, 0.818 mmol) and benzyl bromide (99 μL, 0.818 mmol) in ACN (4.09mL) was stirred at 80° C. for 3 h, then the reaction mixture was cooledto room temperature and treated with sodium triacetoxyhydroborate (520mg, 2.453 mmol). After 1 h the solution was poured into 0.5 M NaOH andextracted twice with EtOAc. The extracts were combined, concentrated,diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR), and purified by HPLC Method A to give the titlecompound as a TFA salt (150 mg, 40.5%).

Preparation 866-benzyl-N-(tert-butyl)-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineN-(tert-butyl)-3-chloropyrido[3,4-b]pyrazin-2-amine

Combined 2,3-dichloropyrido[3,4-b]pyrazine (1 g, 5.00 mmol) and DIPEA(1.75 mL, 10.00 mmol) in DCM (10.00 mL) and cooled to 0° C. and addedtert-butylamine (1.590 mL, 15.00 mmol) and stirred for 48 h. Thereaction mixture was poured into saturated aqueous NH₄Cl and extractedtwice with EtOAc. The organic extracts were combined, filtered throughMgSO₄, and concentrated in vacuo. The residue was redissolved in EtOAc,filtered through a one inch plug of silica, washing with EtOAc, andconcentrated gave N-(tert-butyl)-3-chloropyrido[3,4-b]pyrazin-2-amine(1.04 g, 88%).

A solution of N-(tert-butyl)-3-chloropyrido[3,4-b]pyrazin-2-amine (200mg, 0.845 mmol) and benzyl bromide (145 mg, 0.845 mmol) in ACN (4.22 mL)was heated to 80° C. for 3 h. The reaction was cooled and sodiumtriacetoxyborohydride (537 mg, 2.53 mmol) was added. After 1 h, thereaction was poured into 0.5 M NaOH and extracted twice with EtOAc. Theextracts were combined, concentrated, and purified by HPLC Method A togive the title compound as a TFA salt (125 mg, 33.3%).

Preparation 876-benzyl-3-(4-((2-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A suspension of6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine(117.2 mg, 0.370 mmol) and 4-((2-fluorophenyl)sulfonyl)piperidinehydrochloride (124 mg, 0.444 mmol) in toluene (1.85 mL) was treated withsodium tert-butoxide (107 mg, 1.110 mmol), BINAP (34.6 mg, 0.055 mmol),and Pd₂(dba)₃ (16.9 mg, 0.018 mmol). Nitrogen gas (balloon) was bubbledthrough the reaction mixture for 5 min. The reaction mixture was thensealed and heated at 90° C. for 18 h. The reaction mixture was opened toair and concentrated under reduced pressure. The residue was taken up inDMF/MeOH, filtered through a 0.45 μm syringe filter, and purified byHPLC Method A to give the title compound (99.7 mg, 42.3%). ESI-MS m/z[M+H]⁺ 523.90.

Preparation 886-benzyl-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (73.2mg, 0.280 mmol),6-benzyl-3-chloro-N-cyclopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (100 mg, 0.233 mmol), sodium tert-butoxide (67.2 mg, 0.700mmol), BINAP (21.8 mg, 0.035 mmol) and Pd₂(dba)₃ (10.7 mg, 0.012 mmol)in toluene (1.2 mL) was heated at 90° C. for 14 h. The mixture wasdirectly purified by HPLC Method A to give the title compound as a TFAsalt (114.2 mg, 97%) as a yellow foam. ¹H NMR (400 MHz, methanol-d₄) δppm 0.53-0.60 (m, 2H), 0.78-0.85 (m, 2H), 1.84-1.95 (m, 2H), 1.99-2.09(m, 2H), 2.65-2.73 (m, 1H), 2.90-2.98 (m, 1H), 3.08-3.23 (m, 3H),3.33-3.42 (m, 2H), 3.55-3.68 (m, 2H), 3.75 (s, 3H), 4.16-4.24 (m, 1H),4.28-4.40 (m, 2H), 4.50-4.59 (m, 2H), 6.67 (s, 1H), 6.73 (dd, J=12.9,3.0 Hz, 1H), 7.01-7.09 (m, 1H), 7.52-7.61 (m, 5H); ESI-MS m/z [M+H]⁺504.4.

Preparation 886-benzyl-N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of cyclopropanamine (27.2 mg, 0.477 mmol),6-benzyl-3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazineTFA salt (71.2 mg, 0.119 mmol), sodium tert-butoxide (22.9 mg, 0.239mmol), BINAP (11.1 mg, 0.018 mmol) and Pd₂(dba)₃ (5.5 mg, 5.96 μmol) intoluene (400 μL) was heated at 90° C. for 14 h. The mixture was directlypurified by HPLC Method A to give the title compound as a TFA salt (49.2mg, 66.8%) as a yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ ppm0.50-0.55 (m, 2H), 0.76 (dd, J=7.0, 1.9 Hz, 2H), 1.86-1.96 (m, 2H),2.01-2.10 (m, 2H), 2.63 (tt, J=7.0, 3.6 Hz, 1H), 2.93-3.01 (m, 2H), 3.07(br s, 2H), 3.34-3.41 (m, 2H), 3.56 (br s, 2H), 3.75 (s, 3H), 4.23 (brs, 2H), 4.30-4.37 (m, 1H), 4.53 (br s, 2H,) 6.63-6.68 (m, 1H), 6.73 (dd,J=12.8, 2.9 Hz, 1H), 7.05 (t, J=9.2 Hz, 1H), 7.52-7.61 (m, 5H); ESI-MSm/z [M+H]⁺ 504.4.

Preparation 90N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of6-benzyl-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (5 mg, 8.10 μmol) and Pd(OH)₂ on carbon, (20 wt %, 1 mg, 7.12μmol) in THF (80 μL) was stirred under atmosphere of hydrogen gas(balloon) at rt. After 1 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (4.6 mg, 100%) as a yellow film;ESI-MS m/z [M+H]⁺ 414.4.

Preparation 91N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of6-benzyl-N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (46.8 mg, 0.076 mmol) and Pd(OH)₂ on carbon (20 wt %, 5 mg,0.036 mmol) in THF (760 μL) was stirred under an atmosphere of hydrogengas (balloon) at rt. After 2 h, the mixture was purified by HPLC MethodA to give the title compound as a TFA salt (39.6 mg, 99%) as a yellowoil. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.52-0.59 (m, 2H), 0.75-0.83(m, 2H), 1.84-1.97 (m, 2H), 2.02-2.12 (m, 2H), 2.64-2.71 (m, 1H),2.93-3.16 (m, 4H), 3.35 (s, 2H), 3.52-3.63 (m, 2H), 3.75 (s, 3H),4.20-4.31 (m, 2H), 4.32-4.40 (m, 1H), 6.63-6.69 (m, 1H), 6.73 (dd,J=12.9, 3.0 Hz, 1H), 7.03-7.10 (m, 1H); ESI-MS m/z [M+H]⁺ 414.3.

Preparation 926-benzyl-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 4-((2,4-difluorophenyl)fluoromethyl)piperidinehydrochloride (101 mg, 0.381 mmol),6-benzyl-3-chloro-N-cyclopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine(100 mg, 0.318 mmol), sodium tert-butoxide (92 mg, 0.953 mmol), BINAP(29.7 mg, 0.048 mmol) and Pd₂(dba)₃ (14.5 mg, 0.016 mmol) in toluene(1.6 mL) was heated at 90° C. for 14 h. The mixture was purified by HPLCMethod A to give the title compound as a TFA salt (135.9 mg, 68.8%) as ayellow oil. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.55 (dt, J=3.5, 1.4 Hz,2H), 0.77-0.84 (m, 2H), 1.35-1.43 (m, 1H), 1.50-1.71 (m, 2H), 1.91-2.11(m, 2H), 2.56-2.72 (m, 3H), 3.06-3.15 (m, 2H), 3.36-3.51 (m, 3H),3.52-3.76 (m, 1H), 4.17 (br s, 2H), 4.52 (s, 2H), 5.50 (dd, J=46.2, 7.6Hz, 1H) 6.96-7.07 (m, 2H), 7.44-7.60 (m, 6H); ESI-MS m/z [M+H]⁺ 508.4.

Preparation 93 916-benzyl-N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of cyclopropanamine (65 μL, 0.943 mmol),6-benzyl-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazineTFA salt (141.7 mg, 0.236 mmol), sodium tert-butoxide (45.3 mg, 0.472mmol), BINAP (22.0 mg, 0.035 mmol), and Pd₂(dba)₃ (10.8 mg, 0.012 mmol)in toluene (800 μL) was heated at 90° C. for 14 h. The mixture wasdirectly purified by HPLC Method A to give the title compound as a TFAsalt (98.1 mg, 66.9%) as yellow oil. ¹H NMR (400 MHz, methanol-d₄) δ ppm0.48-0.54 (m, 2H), 0.71-0.78 (m, 2H), 1.36-1.45 (m, 1H), 1.50-1.72 (m,2H), 1.92-2.12 (m, 2H), 2.57-2.71 (m, 3H), 2.97-3.10 (m, 2H), 3.39-3.55(m, 3H), 3.75-3.89 (m, 1H), 4.22 (br s, 2H), 4.53 (br s, 2H), 5.50 (dd,J=46.5, 7.6 Hz, 1H), 6.96-7.07 (m, 2H), 7.45-7.61 (m, 6H); ESI-MS m/z[M+H]⁺ 508.4.

Preparation 94N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of6-benzyl-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (132.1 mg, 0.213 mmol) and Pd(OH)₂ (20 wt %, 15 mg, 0.021 mmol)in THF (1.0 mL) was stirred at room temperature under atmosphere ofhydrogen gas (balloon). After 2 h, the mixture was directly purified byHPLC Method A to give the title compound as a TFA salt (91.1 mg, 81%) asa yellow oil. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.55-0.61 (m, 2H),0.80-0.86 (m, 2H), 1.41 (br d, J=12.4 Hz, 1H), 1.52-1.73 (m, 2 H),1.93-2.13 (m, 2H), 2.60-2.73 (m, 3H), 3.05 (t, J=6.3 Hz, 2H), 3.39-3.52(m, 2H), 3.55 (t, J=6.3 Hz, 2H), 3.98 (s, 1H), 4.17 (s, 2H), 5.51 (dd,J=46.7, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.45-7.54 (m, 1H); ESI-MS m/z[M+H]⁺ 418.3.

Preparation 95N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of6-benzyl-N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (93.5 mg, 0.150 mmol) and Pd(OH)₂ (20 wt %, 10 mg, 0.014 mmol)in THF (750 μL) was stirred at room temperature under an atmosphere ofhydrogen gas (balloon). After 2 h, the mixture was directly purified byHPLC Method A to give the title compound as a TFA salt (67.7 mg, 85%) asa yellow oil. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.51-0.57 (m, 2H),0.75-0.81 (m, 2H), 1.43 (br d, J=13.1 Hz, 1H), 1.52-1.72 (m, 2H),1.94-2.13 (m, 2H), 2.59-2.72 (m, 3H), 2.97 (t, J=6.3 Hz, 2H), 3.40-3.50(m, 2H), 3.51-3.56 (m, 2H), 3.98 (s, 1H), 4.22 (s, 2H), 5.51 (dd,J=46.2, 7.3 Hz, 1H), 6.96-7.08 (m, 2H), 7.46-7.54 (m, 1H); ESI-MS m/z[M+H]⁺ 418.3.

Preparation 966-benzyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (72.9mg, 0.279 mmol),6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (100 mg, 0.232 mmol), sodium tert-butoxide (66.9 mg, 0.696mmol), BINAP (21.7 mg, 0.035 mmol), and Pd₂(dba)₃ (10.6 mg, 0.012 mmol)in toluene (1.16 mL) was heated at 100° C. in a sealed tube for 14 h.The mixture was purified by HPLC Method A to give the title compound asa TFA salt (122.1 mg, 85%) as a yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.86-1.97 (m, 2H), 2.03-2.12(m, 2H), 2.95 (br s, 2H), 3.01-3.12 (m, 2H), 3.33-3.38 (m, 2H), 3.53 (brs, 2H), 3.75 (s, 3H), 4.13-4.24 (m, 3H), 4.31-4.38 (m, 1H), 4.52 (s,2H), 6.63-6.69 (m, 1H), 6.73 (dd, J=12.8, 2.9 Hz, 1H), 7.06 (t, J=9.2Hz, 1H), 7.51-7.60 (m, 5H); ESI-MS m/z [M+H]⁺ 506.4.

Preparation 976-benzyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 4-((2,4-difluorophenyl)fluoromethyl)piperidinehydrochloride (74.0 mg, 0.279 mmol),6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (100 mg, 0.232 mmol), sodium tert-butoxide (66.9 mg, 0.696mmol), BINAP (21.7 mg, 0.035 mmol) and Pd₂(dba)₃ (10.6 mg, 0.012 mmol)in toluene (1.2 mL) was heated at 100° C. in a sealed tube for 14 h. Themixture was purified by HPLC Method A to give the title compound as aTFA salt (108.3 mg, 74.8%) as a yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.23 (dd, J=6.4, 2.4 Hz, 6H), 1.39-1.47 (m, 1H),1.51-1.72 (m, 2H), 1.95-2.12 (m, 2H), 2.58-2.70 (m, 2H), 3.04 (br s,2H), 3.36-3.83 (m, 4H), 4.09-4.21 (m, 3H), 4.51 (br s, 2H), 5.52 (dd,J=46.2, 7.3 Hz, 1H), 6.97-7.07 (m, 2H), 7.45-7.59 (m, 6H); ESI-MS m/z[M+H]⁺ 510.4.

Preparation 983-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of6-benzyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (122 mg, 0.197 mmol) and Pd(OH)₂ on carbon (20 wt %, 12 mg,0.017 mmol) in THF (2.0 mL) was stirred under an atmosphere of hydrogengas (balloon) at rt. After 2 h, the mixture was purified by HPLC MethodA to give the title compound as a TFA salt (83.2 mg, 80%) as a yellowoil. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.25 (d, J=6.6 Hz, 6H),1.88-1.98 (m, 2H), 2.04-2.13 (m, 2H), 2.93-3.03 (m, 4H), 3.35-3.41 (m,3H), 3.54 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 4.14-4.18 (m, 2H), 4.18-4.23(m, 1H), 4.32-4.40 (m, 1H), 6.67 (ddd, J=9.0, 3.0, 1.4 Hz, 1H), 6.74(dd, J=12.9, 3.0 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]⁺416.3.

Preparation 993-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of6-benzyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (108.3 mg, 0.174 mmol) and Pd(OH)₂ on carbon, (20 wt %, 11 mg,0.016 mmol) in THF (1.7 mL) was stirred under an atmosphere of hydrogengas (balloon) at rt. After 2 h, the mixture was purified by HPLC MethodA to give the title compound as a TFA salt (67.5 mg, 72.9%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.24 (dd, J=6.6, 2.3 Hz, 6H),1.41-1.48 (br m, 1H), 1.52-1.74 (m, 2H), 1.97-2.14 (m, 2H), 2.61-2.73(m, 2H), 2.99 (t, J=6.3 Hz, 2H), 3.38-3.49 (m, 2H), 3.50-3.55 (m, 2H),4.14 (s, 2H), 4.14-4.21 (m, 1H), 5.53 (dd, J=46.5, 7.3 Hz, 1H),6.95-7.10 (m, 2H), 7.46-7.55 (m, 1H); ESI-MS m/z [M+H]⁺ 420.3.

Preparation 1006-benzyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of propan-2-amine (71 μL, 0.827 mmol),6-benzyl-3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazineTFA salt (123.4 mg, 0.207 mmol), sodium tert-butoxide (39.7 mg, 0.413mmol), BINAP (19.3 mg, 0.031 mmol) and Pd₂(dba)₃ (9.5 mg, 10.33 μmol) intoluene (690 μL) was heated at 100° C. for 16 h. The mixture was thenpurified by HPLC Method A to give the title compound as a TFA salt (54.7mg, 42.7%) as a yellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.22(d, J=6.6 Hz, 6H), 1.87-2.13 (m, 4H), 2.94-3.10 (m, 4H), 3.35-3.53 (m,3H), 3.75 (s, 3H), 3.79-3.88 (m, 1H), 4.07-4.27 (m, 3H), 4.31-4.39 (m,1H), 4.52 (br s, 2H), 6.66 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.73 (dd,J=12.9, 3.0 Hz, 1H), 7.03-7.10 (m, 1H), 7.51-7.60 (m, 5H); ESI-MS m/z[M+H]⁺ 506.4.

Preparation 1016-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of propan-2-amine (82 μL, 0.954 mmol),6-benzyl-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazineTFA (143.3 mg, 0.238 mmol), sodium tert-butoxide (45.8 mg, 0.477 mmol),BINAP (22.3 mg, 0.036 mmol) and Pd₂(dba)₃ (10.9 mg, 0.012 mmol) intoluene (800 μL) at 100° C. for 16 h. The mixture was then purified byHPLC Method A to give the title compound as a TFA salt (63.8 mg, 42.9%)as a yellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.21 (dd, J=6.4,2.4 Hz, 6H), 1.40-1.48 (m, 1H), 1.51-1.74 (m, 2H), 1.95-2.16 (m, 2H),2.61-2.73 (m, 2H), 3.00 (br s, 2H), 3.40-3.57 (m, 3H), 4.06-4.13 (m,2H), 4.15-4.20 (br m, 1H), 4.51 (br s, 2H), 5.52 (dd, J=46.0, 7.3 Hz,1H), 6.97-7.08 (m, 2H), 7.46-7.62 (m, 6H); ESI-MS m/z [M+H]⁺ 510.4.

Preparation 1022-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of6-benzyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (51 mg, 0.082 mmol) and Pd(OH)₂ on carbon (20 wt %, 5 mg, 7.12μmol) in THF (820 μL) was stirred under an atmosphere of hydrogen gas(balloon) at rt. After 2 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (41.2 mg, 95%) as a yellow foam.¹H NMR (400 MHz, methanol-d₄) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.88-1.98(m, 2H), 2.05-2.14 (m, 2H), 2.94-3.03 (m, 4H), 3.35-3.43 (m, 2H), 3.54(t, J=6.3 Hz, 2H), 3.76 (s, 3H), 4.10-4.21 (m, 3H), 4.32-4.39 (m, 1H),6.67 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.07(t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]⁺ 416.3.

Preparation 1032-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of6-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (60 mg, 0.096 mmol) and Pd(OH)₂ on carbon, (20 wt %, 6 mg, 8.54μmol) in THF (960 μL) was stirred under an atmosphere of hydrogen gas(balloon) at rt. After 2 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (47.6 mg, 93%) as a yellow foam.¹H NMR (400 MHz, methanol-d₄) δ ppm 1.23 (dd, J=6.4, 2.4 Hz, 6H),1.41-1.49 (m, 1H), 1.52-1.74 (m, 2H), 1.98-2.14 (m, 2H), 2.68 (qd,J=12.6, 2.5 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 3.40-3.51 (m, 2H), 3.52 (t,J=6.3 Hz, 2H), 4.10-4.16 (m, 1H), 4.16 (s, 2H), 5.53 (dd, J=46.5, 7.6Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]⁺ 420.3.

Preparation 1042-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(6.43 g, 13.03 mmol) and 10% Pd/C (640 mg) in MeOH (86 mL) under H₂ in aballoon was stirred at room temperature overnight. Removal of thesolvent gave the title compound (4.4 g, 84%) as a yellow oil. ¹H NMR(400 MHz, methanol-d₄) δ ppm 1.24 (d, J=6.4 Hz, 6H), 1.89-1.99 (m, 2H),2.09-2.17 (m, 2H), 2.74 (t, J=5.9 Hz, 2H), 2.95 (ddd, J=12.3, 8.7, 3.4Hz, 2H), 3.11 (t, J=6.1 Hz, 2H), 3.82 (s, 2H), 4.14 (septet, J=6.4 Hz,1H), 4.46 (tt, J=7.7, 3.5 Hz, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.4,8.4, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 404.0.

Preparation 1052-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

To a solution of1-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone(0.367 g, 0.826 mmol) in MeOH (4 mL) was added NaOH, 15% solution (2.201g, 8.26 mmol) at 23° C. The reaction mixture was stirred at 65° C. for16 hr, cooled to 23° C., and neutralized with 1N HCl (9.5 mL) to furnisha suspension. The crude mixture was concentrated via rotary evaporation,cooled to 23° C., and stirred overnight. The resulting solid wasfiltered, rinsed with water, and dried in vacuo to give the titlecompound (253 mg, 76%) as a yellow foam. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.15 (d, J=6.8 Hz, 6H), 2.42 (br s, 1H), 2.51-2.61 (m, 6H), 2.89-3.00(m, 6H), 3.58 (s, 2H), 3.63 (s, 2H), 4.00-4.10 (m, 1H), 5.15 (d, J=8.3Hz, 1H), 7.04-7.11 (m, 1H), 7.21 (td, J=10.0, 2.4 Hz, 1H), 7.44-7.52 (m,1H); ESI-MS m/z [M+H]⁺ 403.0.

Preparation 1064-((1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile

A mixture of6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineacetate (2.765 g, 2.93 mmol), 3-fluoro-4-(piperidin-4-yloxy)benzonitrilehydrochloride (0.904 g, 3.52 mmol), sodium tert-butoxide (1.128 g, 11.74mmol), BINAP (0.274 g, 0.440 mmol), and Pd₂(dba)₃ (0.134 g, 0.147 mmol)in toluene (25 mL) was stirred at 100° C. for 22 h. Additional portionsof BINAP (0.219 g, 0.352 mmol) and Pd₂(dba)₃ (0.107 g, 0.117 mmol) wereadded to the flask and the reaction mixture was stirred for anadditional 2 days at 100° C. The mixture was cooled to 23° C., filteredthrough Celite™ rinsed with toluene, and the filtrate was concentratedvia rotary evaporation. The crude material was dissolved in DMSO (10mL), filtered, rinsed with DMSO, and purified by HPLC Method B, with theexception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used,using an ACN gradient of 30% to 70% to give the title compound as a TFAsalt (581 mg, 32.2% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.05-1.33 (m, 6H), 1.81-1.96 (m, 2H), 2.08-2.18 (m, 2H), 2.84-3.00(m, 3H), 3.01-3.17 (m, 1H), 3.18-3.32 (m, 2H), 3.33-3.46 (m, 1H),3.65-3.77 (m, 1H), 3.95-4.06 (m, 1H), 4.08-4.30 (m, 2H), 4.43-4.57 (m,2H), 4.80-4.87 (m, 1H), 5.91 (d, J=8.1 Hz, 1H), 7.44-7.60 (m, 6H),7.66-7.70 (m, 1H), 7.84-7.90 (m, 1H), 10.13 (br s, 1H); ESI-MS m/z[M+H]⁺ 501.5.

Preparation 1073-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile

A mixture of4-((1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile2,2,2-trifluoroacetate (579 mg, 0.942 mmol) and Pd(OH)₂ (20 wt % Pd (drybasis) on carbon, wet, Degussa Type E101 NE/W, 198 mg, 0.283 mmol) inTHF (10 mL) was stirred under H₂ (1.899 mg, 0.942 mmol) at 23° C. for 4h. The mixture was filtered, rinsed with THF, concentrated via rotaryevaporation, and dried in vacuo to give the title compound as a TFA salt(494 mg, 100%) as a brown oil. ESI-MS m/z [M+H]⁺ 411.4.

Preparation 108(5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone

A mixture of (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanonehydrochloride (69.7 mg, 0.251 mmol),6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (90 mg, 0.209 mmol), sodium tert-butoxide (60.2 mg, 0.627mmol), BINAP (19.5 mg, 0.031 mmol) and Pd₂(dba)₃ (9.6 mg, 10.4 μmol) intoluene (1.04 mL) was heated at 100° C. for 16 h. The mixture waspurified by HPLC Method A to afford(1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanoneas its TFA salt (48.9 mg, 36.8%) as a yellow oil. ESI-MS m/z [M+H]⁺523.4.

A mixture of(1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanoneTFA salt (48.9 mg, 0.077 mmol) and Pd(OH)₂ on carbon (20 wt %, 5 mg,0.036 mmol) in THF (384 μL) was stirred at rt under an atmosphere ofhydrogen gas (balloon). After 3 h, the mixture was diluted with MeOH,filtered through a pad of Celite™, washing with MeOH, and concentratedto afford he title compound as its TFA salt (37.1 mg, 88%) as a yellowfilm, which was used without further purification. ESI-MS m/z [M+H]⁺432.3.

Preparation 1093-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 4-(2,4-difluorophenoxy)piperidine hydrochloride (62.6 mg,0.251 mmol),6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (90 mg, 0.209 mmol), sodium tert-butoxide (60.2 mg, 0.627mmol), BINAP (19.5 mg, 0.031 mmol) and Pd₂(dba)₃ (9.6 mg, 10.4 μmol) intoluene (1.04 mL) was heated at 100° C. for 16 h. The mixture waspurified by HPLC Method A to afford6-benzyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas its TFA salt (73.0 mg, 57.5%) as a yellow oil. ESI-MS m/z [M+H]⁺494.4.

A mixture of6-benzyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (73.0 mg, 0.120 mmol) and Pd(OH)₂ on carbon (20 wt %, 7 mg,9.97 μmol) in THF (601 μL) was stirred at rt under an atmosphere ofhydrogen (balloon). After 3 h, the mixture was diluted with MeOH,filtered through a pad of Celite™, washing with MeOH, and concentratedto afford the title compound as its TFA salt (62.3 mg, 100%) as a yellowoil, which was used without further purification. ESI-MS m/z [M+H]⁺404.3.

Preparation 110N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution of6-benzyl-3-chloro-N-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (150 mg, 0.331 mmol), 4-(2,4-difluorophenoxy)piperidinehydrochloride (99 mg, 0.398 mmol), Pd₂(dba)₃ (15.2 mg, 0.017 mmol),BINAP (20.63 mg, 0.033 mmol), and sodium tert-butoxide (96 mg, 0.994mmol), in toluene (1104 μL) was stirred at 90° C. overnight. The solventwas removed and the crude product diluted in DMF, filtered through ahydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purifiedvia HPLC Method A to give6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (152 mg).

A solution of6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (152 mg, 0.241 mmol) and Pd(OH)₂ on carbon (33.9 mg, 0.048mmol) in THF (2.41 mL) was purged with and placed under hydrogen(balloon) atmosphere at room temperature for 2 h. The mixture was thenfiltered through Celite™ and concentrated to give the title compound asa TFA salt (115 mg, 0.213 mmol).

Preparation 111N-(tert-butyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution of sodium tert-butoxide (81 mg, 0.843 mmol),6-benzyl-N-(tert-butyl)-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (125 mg, 0.281 mmol), Pd₂(dba)₃ (12.86 mg, 0.014 mmol),4-(2,4-difluorophenoxy)piperidine hydrochloride (84 mg, 0.337 mmol), andBINAP (17.50 mg, 0.028 mmol) in toluene (937 μL) was stirred at 90° C.overnight. The crude reaction mixture was diluted in DMF, filteredthrough a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), andpurified via HPLC Method A to give6-benzyl-N-(tert-butyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (155 mg).

A solution of6-benzyl-N-(tert-butyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (155 mg, 0.249 mmol) and Pd(OH)₂ on carbon (35.0 mg, 0.050mmol) in THF (2.49 mL) was purged and placed under hydrogen (balloon)atmosphere for 2 h. Filtration through Celite™ and concentration gavethe title compound as a TFA salt (125 mg).

Preparation 112N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol),cyclobutanamine (47.0 μL, 0.550 mmol) and DIPEA (260 μL, 1.500 mmol) wasstirred at 0° C. for 15 min then at rt for 30 min. Saturated aqueousNH₄Cl was added to the mixture and the product was extracted with EtOAc.The combined organic layers were filtered through a pad of silica (EtOAcwash) and the filtrate was concentrated to afford3-chloro-N-cyclobutylpyrido[3,4-b]pyrazin-2-amine (116.1 mg, 99%) as ayellow solid, which was used without further purification. ESI-MS m/z[M+H]⁺ 235.2.

A mixture of 3-chloro-N-cyclobutylpyrido[3,4-b]pyrazin-2-amine (116 mg,0.494 mmol) and benzyl bromide (59.1 μL, 0.494 mmol) in ACN (2.47 mL)was heated at 80° C. for 3 h. After cooling to rt, the mixture wastreated with sodium triacetoxyborohydride (314 mg, 1.483 mmol) at rt.The mixture was purified by HPLC Method A to afford6-benzyl-3-chloro-N-cyclobutyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas its TFA salt (135.3 mg, 61.8%) as a yellow solid. ESI-MS m/z [M+H]⁺329.3.

A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (56.7mg, 0.217 mmol),6-benzyl-3-chloro-N-cyclobutyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (80 mg, 0.181 mmol), sodium tert-butoxide (52.1 mg, 0.542mmol), BINAP (16.9 mg, 0.027 mmol) and Pd₂(dba)₃ (24.8 mg, 0.027 mmol)in toluene (602 μL) was heated at 90° C. in a sealed tube for 16 h. Themixture was purified by HPLC Method A to afford6-benzyl-N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas its TFA salt (85.2 mg, 74.7%) as a yellow foam. ESI-MS m/z [M+H]⁺518.4.

A mixture of6-benzyl-N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (85.2 mg, 0.135 mmol) and Pd(OH)₂ on carbon (10 mg, 0.071 mmol)in THF (674 μL) was stirred at rt under an atmosphere of hydrogen gas(balloon). After 4 h, the mixture was filtered, washing with MeOH, andconcentrated to afford the title compound as its TFA salt (73 mg, 100%)as a yellow solid, which was used without further purification. ESI-MSm/z [M+H]⁺ 428.4.

Preparation 113N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

2,3-Dichloro-5-methylpyrido[3,4-b]pyrazine (1.700 g, 7.94 mmol) wasadded to dioxane (15.88 mL), then cyclopropanamine (0.864 mL, 12.71mmol) and DIPEA (2.24 mL, 13.50 mmol) were added sequentially. Themixture was stirred for 12 h at room temperature then concentrated underreduced pressure. Column chromatography using a gradient of 10% to 75%EtOAc in hexanes provided3-chloro-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine (1.3 g) as abrown solid.

Combined 3-chloro-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine(350 mg, 1.491 mmol) and benzyl bromide (177 μL, 1.491 mmol) in ACN(5.97 mL) was heated at 80° C. overnight, then cooled to roomtemperature and sodium triacetoxyborohydride (948 mg, 4.47 mmol) wasadded. After stirring for 1 h, the reaction mixture was poured into 1 MNaOH, extracted with ethyl acetate (2×), concentrated in vacuo, andpurified by HPLC Method A gave6-benzyl-3-chloro-N-cyclopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (424 mg).

Combined6-benzyl-3-chloro-N-cyclopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (106 mg, 0.239 mmol), 4-(2,4-difluorophenoxy)piperidinehydrochloride (65.7 mg, 0.263 mmol), Pd₂(dba)₃ (21.9 mg, 0.024 mmol),sodium tert-butoxide (57.5 mg, 0.598 mmol), and BINAP (29.8 mg, 0.048mmol) in toluene (798 μL) was heated at 90° C. overnight. Purificationby HPLC Method A gave6-benzyl-N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (110 mg).

Combined6-benzyl-N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (110 mg, 0.178 mmol) and Pd(OH)₂ (20 wt %, 12.5 mg, 0.018 mmol)in THF (888 μL) was purged with hydrogen and allowed to stir underhydrogen (balloon) overnight. The reaction mixture was filtered throughCelite™, washed with EtOAc, and concentrated under reduced pressure togive the title compound as a TFA salt (78 mg).

Preparation 1143-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution of6-benzyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (150 mg, 0.241 mmol) and Pd(OH)₂ on carbon (16.9 mg, 0.024mmol) in THF (1.21 mL) was purged and placed under hydrogen atmosphere(balloon) overnight. The mixture was then filtered through Celite™ andconcentrated to give the title compound as its TFA salt (132 mg).

Preparation 115N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution of6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (160 mg, 0.249 mmol) and Pd(OH)₂ on carbon (17.5 mg, 0.025mmol) in THF (1.24 mL) was purged and placed under hydrogen atmosphere(balloon) overnight. The mixture was filtered through Celite™ andconcentrated to give title compound as its TFA salt (136 mg).

Preparation 116N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution of 2,3-dichloro-7-methylpyrido[3,4-b]pyrazine (125 mg, 0.584mmol), 2,2-difluoroethanamine (53.6 μL, 0.701 mmol), and DIPEA (306 μL,1.752 mmol) in DCM (1.17 mL) was stirred at room temperature for 48 h,then poured into a saturated aqueous solution of NH₄Cl and extractedtwice with EtOAc. The extracts were combined, filtered through MgSO₄,and concentrated to give3-chloro-N-(2,2-difluoroethyl)-7-methylpyrido[3,4-b]pyrazin-2-amine (143mg, 95%).

A solution of3-chloro-N-(2,2-difluoroethyl)-7-methylpyrido[3,4-b]pyrazin-2-amine (143mg, 0.553 mmol) and benzyl bromide (65.8 μL, 0.553 mmol) in ACN (2.76mL) was stirred at 100° C. overnight, cooled to room temperature, thentreated with sodium triacetoxyhydroborate (352 mg, 1.659 mmol) andstirred for 3 h. The mixture was poured into 1 M NaOH, extracted twicewith EtOAc, and the EtOAc extracts were combined and concentrated. Thecrude material was diluted in DMF, filtered through a hydrophilic PTFE0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method Ato give6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (120 mg, 46.5%).

A solution of6-benzyl-3-chloro-N-(2,2-difluoroethyl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (120 mg, 0.257 mmol), 4-(2,4-difluorophenoxy)piperidinehydrochloride (77 mg, 0.308 mmol), Pd₂(dba)₃ (23.5 mg, 0.026 mmol),BINAP (32.0 mg, 0.051 mmol), and sodium tert-butoxide (74.1 mg, 0.771mmol), in toluene (1.28 mL) was stirred at 100° C. overnight. The crudereaction mixture was diluted in DMF, filtered through a hydrophilic PTFE0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method Ato give6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (135 mg, 82%).

A solution of6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (135 mg, 0.210 mmol) and Pd(OH)₂ on carbon (14.7 mg, 0.021mmol) in THF (1.05 mL) was purged and stirred under hydrogen atmospherefor 3 h. The reaction mixture was filtered through Celite™ and thesolvent was removed to give the title compound as a TFA salt (107 mg,92%).

EXAMPLE 1Cyclopropyl(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone

To a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (18.0 mg, 0.035 mmol) in DCM (348 μL) at room temperature wasadded triethylamine (14.5 μL, 0.104 mmol) and cyclopropanecarbonylchloride (6.4 μL, 0.070 mmol). The reaction was stirred for 10 min atroom temperature. The reaction mixture was concentrated under reducedpressure and was purified by HPLC Method B, with the exception that aWaters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 50% to90% ACN gradient to give the title compound, as a TFA salt, as a yellowfilm (3.3 mg, 16%). ¹H NMR (400 MHz, methanol-d4, mixture of rotamers) δppm 0.81-0.96 (m, 4H), 1.29 (m, 7H), 1.90-2.18 (m, 4H), 2.73 (m, 0.7H),2.87 (m, 1.3H), 3.07 (m, 2H), 3.42 (m, 2H), 3.88 (m, 0.7H), 4.06 (t,J=5.7 Hz, 1.3H), 4.14 (m, 1H), 4.49 (m, 1H), 4.62 (s, 1.3H), 4.80 (s,0.7H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 ppm (td,J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 472.5.

EXAMPLE 21-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethan-1-one

To a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (39.0 mg, 0.075 mmol) in DCM (754 μL) at 0° C. was addedtriethylamine (31.5 μL, 0.226 mmol) and 2-methoxyacetyl chloride (13.8μL, 0.151 mmol). The reaction was stirred at 0° C. for 30 min. Thereaction mixture was concentrated under reduced pressure and waspurified by HPLC Method B, with the exception that a Waters SunFire™C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradientto give the title compound, as a TFA salt, as a yellow oil (14.0 mg,31.5%). ¹H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.30(m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.75 (t, J=5.7 Hz, 0.7H), 2.83 (t,J=5.7 Hz, 1.3H), 3.08 (m, 2H), 3.44 (m, 5H), 3.77 (t, J=5.8 Hz, 1.3H),3.88 (t, J=5.9 Hz, 0.7H), 4.14 (m, 1H), 4.24 (s, 0.7H), 4.28 (s, 1.3H),4.49 (td, J=7.1, 3.5 Hz, 1H), 4.56 (s, 0.7H), 4.63 (s, 1.3H), 6.88 (m,1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 476.5.

EXAMPLE 32-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (735.3 mg, 1.421 mmol) in DCM (14.2 mL) at 0° C. was treatedwith triethylamine (0.594 mL, 4.26 mmol), followed by methanesulfonylchloride (0.221 mL, 2.84 mmol). The reaction mixture was stirred at 0°C. for 1 h. The reaction mixture was concentrated under reducedpressure. The residue was taken up in MeOH, filtered through aMillipore® 0.45 μm syringe filter, and purified by HPLC Method A. Thecorresponding fractions were collected and concentrated under reducedpressure. The resulting residue was taken up in DCM and washed withsaturated aqueous K₂CO₃ to generate the free base. The organic layer wasseparated, dried over Na₂SO₄, and filtered. Evaporation of the filtrateand lyophilization gave the title compound as an off-white solid (229.6mg, 33.6%). ¹H NMR (500 MHz, DMSO-d6) 1.18 (d, J=6.3 Hz, 6H), 1.88 (m,2H), 2.07 (m, 2H), 2.75 (t, J=5.9 Hz, 2H), 2.89 (m, 2H), 2.97 (s, 3H),3.29 (m, 2H), 3.45 (t, J=5.9 Hz, 2H), 4.09 (m, 1H), 4.16 (s, 2H), 4.52(tt, J=8.1, 3.9 Hz, 1H), 5.57 (d, J=8.3 Hz, 1H), 7.01 (m, 1H), 7.30 (m,2H); ESI-MS m/z [M+H]⁺ 481.90.

EXAMPLE 42-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-N-(2-methoxyethyl)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

To a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (39.0 mg, 0.075 mmol) in DCM (754 μL) at 0° C. was addedtriethylamine (31.5 μL, 0.226 mmol) and 1-isocyanato-2-methoxyethane(11.8 μL, 0.113 mmol). The reaction mixture was stirred for 1 h at 0° C.The reaction mixture was concentrated under reduced pressure andpurified by HPLC Method B, with the exception that a Waters SunFire™C18, 5 μm, ID 30×75 mm column was used, using a 45% to 70% ACN gradientto give the title compound, as a TFA salt, as a yellow oil (24.5 mg,52.6%). ¹H NMR (400 MHz, methanol-d4) δ ppm 1.32 (d, J=6.6 Hz, 6H), 1.97(m, 2H), 2.14 (m, 2H), 2.77 (t, J=5.8 Hz, 2H), 3.12 (m, 2H), 3.37 (m,5H), 3.46 (m, 4H), 3.71 (t, J=5.8 Hz, 2H), 4.13 (m, 1H), 4.50 (m, 3H),6.88 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6Hz, 1H); ESI-MS m/z [M+H]⁺ 505.6.

EXAMPLE 5(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(tetrahydrofuran-2-yl)methanone

To a solution of tetrahydrofuran-2-carboxylic acid (10.9 μL, 0.113 mmol)in DMA (0.35 mL) at room temperature was added DIPEA (39.5 μL, 0.226mmol), followed by HATU (43.0 mg, 0.113 mmol). After stirring for 5 min,the reaction mixture was treated with a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (39.0 mg, 0.075 mmol) in DMA (0.4 mL). The reaction mixture wasstirred at 60° C. for 30 min. The reaction mixture was allowed to coolto room temperature and was purified directly by HPLC Method B, with theexception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used,using a 55% to 80% ACN gradient to give the title compound, as a TFAsalt, as a yellow oil (16.0 mg, 34.5%). ¹H NMR (400 MHz, methanol-d4) δppm 1.31 (m, 6H), 1.97 (m, 4H), 2.16 (m, 4H) 2.82 (m, 2H), 3.10 (m, 2H),3.45 (m, 2H), 3.89 (m, 4H), 4.14 (m, 1H), 4.44-4.87 (m, 4H), 6.88 (m,1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H);ESI-MS m/z [M+H]⁺ 502.6.

EXAMPLE 63-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-3-oxopropanenitrile

To a solution of 2-cyanoacetic acid (8.3 mg, 0.097 mmol) in DMA (0.3 mL)at room temperature was added DIPEA (33.9 μL, 0.194 mmol), followed byHATU (36.9 mg, 0.097 mmol). This mixture was stirred for 5 min, then wastreated with a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (33.5 mg, 0.065 mmol) in DMA (0.35 mL). The reaction mixturewas heated at 60° C. for 30 min. The reaction mixture was purifieddirectly by HPLC Method B, with the exception that a Waters SunFire™C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradientto give the title compound, as a TFA salt, as a yellow oil (5.5 mg,14%). ¹H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (m,6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.75 (t, J=5.9 Hz, 0.8H), 2.85 (m,1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.75 (t, J=5.8 Hz, 1.2H), 3.89 (t,J=5.9 Hz, 0.8H), 4.00 (m, 2H); 4.14 (m, 1H), 4.48 (m, 1H), 4.50 (s,0.8H), 4.60 (s, 1.2H), 6.88 (m, 1H), 6.98 (ddd, J=11.4, 8.6, 3.0 Hz,1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 471.5.

EXAMPLE 74-((1-(6-acetyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile

To a solution of3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (33.5 mg, 0.064 mmol) in DCM (639 μL) at 0° C. was addedpyridine (15.5 μL, 0.192 mmol), followed by acetic anhydride (12.0 μL,0.128 mmol). The reaction was allowed to stir for 45 min, graduallywarming to room temperature. The reaction was concentrated under reducedpressure and purified directly by HPLC Method B, with the exception thata Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 40% to70% ACN gradient to give the title compound, as a TFA salt, as a yellowsolid (7.1 mg, 20%). ¹H NMR (400 MHz, methanol-d4, mixture of rotamers)δ ppm 1.31 (m, 6H), 2.02 (m, 2H), 2.20 (m, 5H), 2.74 (t, J=5.9 Hz,0.7H), 2.85 (m, 1.3H), 3.14 (m, 2H), 3.43 (m, 2H), 3.83 (t, J=5.9 Hz,1.3H), 3.87 (t, J=5.9 Hz, 0.7H), 4.14 (m, 1H), 4.60 (s, 0.7H), 4.64 (s,1.3H), 4.80 (m, 1H), 7.34 (m, 1H), 7.54 (m, 2H); ESI-MS m/z [M+H]⁺453.5.

EXAMPLE 81-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-1-one

To a solution of 2-methoxypropanoic acid (10.8 μL, 0.113 mmol) in DMA(0.4 mL) at room temperature was added DIPEA (45.5 μL, 0.261 mmol) andHATU (42.9 mg, 0.113 mmol). To this was added a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (45.0 mg, 0.087 mmol) in DMA (0.47 mL). The resulting reactionmixture was stirred at 60° C. for 45 min. The reaction mixture wasallowed to cool to room temperature and was purified directly by HPLCMethod B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75mm column was used, using a 50% to 80% ACN gradient to give the titlecompound, as a TFA salt, as a pale yellow solid (11.2 mg, 21.4%). ¹H NMR(400 MHz, methanol-d4) δ ppm 1.36 (m, 9H), 1.98 (m, 2H), 2.14 (m, 2H),2.83 (m, 2H), 3.16 (m, 2H), 3.35 (s, 3H), 3.49 (m, 2H), 3.90 (m, 1H),3.93 (t, J=5.8 Hz, 1H), 4.12 (m, 1H), 4.35 (m, 1H), 4.52 (m, 1H),4.59-4.79 (m, 2H), 6.88 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H),7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 490.5.

EXAMPLE 9Cyclopropyl(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone

To a solution of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine2TFA salt (34.2 mg, 0.059 mmol) and triethylamine (0.025 mL, 0.178 mmol)in DCM (0.5 mL) was added cyclopropanecarboxylic acid chloride (10.8 μL,0.119 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30min and then concentrated via rotary evaporation. The crude material wasdiluted with DMSO, filtered, rinsed with DMSO, and purified by HPLCMethod B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID4.6×50 mm was used, using an ACN gradient of 30% to 70% to give thetitle compound as a TFA salt (17.7 mg, 51.0%) as a yellow oil. ¹H NMR(400 MHz, DMSO-d₆, mixture of rotamers) δ ppm 0.67-0.81 (m, 4H), 1.19(d, J=6.3 Hz, 6H), 1.80-1.95 (m, 2H), 2.01-2.07 (m, 2H), 2.51-2.56 (m,1H), 2.57-2.66 (m, 0.9H), 2.72-2.79 (m, 1.1H), 2.84-2.94 (m, 2H),3.23-3.33 (m, 2H), 3.70-3.79 (m, 0.9H), 3.92-3.98 (m, 1.1H), 4.08-4.18(m, 1H), 4.42 (br s, 1.1H), 4.48-4.56 (m, 1H), 4.67 (br s, 0.9H), 5.71(br s, 1H), 6.99-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]⁺472.5.

EXAMPLE 101-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethan-1-one

To a solution of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (34.2 mg, 0.059 mmol) and triethylamine (0.025 mL, 0.178 mmol)in DCM (0.5 mL) was added methoxyacetyl chloride (10.8 μL, 0.119 mmol)at 0° C. The reaction mixture was stirred at 0° C. for 30 min and thenconcentrated via rotary evaporation. The crude material was diluted withDMSO, rinsed with DMSO, and purified by HPLC Method B, with theexception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used,using an ACN gradient of 30% to 70% to give the title compound as a TFAsalt (19.0 mg, 54.4%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆, mixtureof rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.83-1.93 (m, 2H), 2.03-2.11(m, 2H), 2.63 (t, J=5.8 Hz, 0.9H), 2.72 (t, J=5.3 Hz, 1.1H), 2.84-2.93(m, 2H), 3.22-3.36 (m, 5H), 3.66 (t, J=5.8 Hz, 1.1H), 3.74 (t, J=6.1 Hz,0.9H), 4.10-4.16 (m, 1H), 4.17 (br s, 0.9H), 4.19 (s, 1.1H), 4.49-4.56(m, 1H), 5.65-5.72 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.35 (m, 2H); ESI-MSm/z [M+H]⁺ 476.5.

EXAMPLE 113-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

To a solution of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (34.2 mg, 0.059 mmol) and triethylamine (0.025 mL, 0.178 mmol)in DCM (0.5 mL) was added methanesulfonyl chloride (6.9 μL, 0.089 mmol)at 0° C. The reaction mixture was stirred at 0° C. for 30 min and thenconcentrated via rotary evaporation. The crude material was diluted withDMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, withthe exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm wasused, using an ACN gradient of 30% to 70% to give the title compound asa TFA salt (14.7 mg, 41.6%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.19 (d, J=6.6 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.08 (m, 2H), 2.77(t, J=5.7 Hz, 2H), 2.84-2.93 (m, 2H), 2.98 (s, 3H), 3.24-3.32 (m, 2H),3.45 (t, J=5.9 Hz, 2H), 4.10-4.18 (m, 3H), 4.50-4.55 (m, 1H), 5.67 (brs, 1H), 6.99-7.04 (m, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]⁺ 482.4.

EXAMPLE 122-(4-(4-cyano-2-fluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A solution of3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (32.5 mg, 0.062 mmol) in DCM (620 μL) at 0° C. was treated withtriethylamine (25.9 μL, 0.186 mmol) and dimethylcarbamic chloride (11.4μL, 0.124 mmol). The reaction mixture was allowed to gradually warm toroom temperature and stir for 1 h. The reaction mixture was concentratedunder reduced pressure and purified directly by HPLC Method B, with theexception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used,using a 40% to 70% ACN gradient to give the title compound in (about 90%purity), as a TFA salt, as a yellow solid (6.8 mg, 18%). ¹H NMR (400MHz, methanol-d4) δ ppm 1.29 (m, 6H), 2.02 (m, 2H), 2.19 (m, 2H), 2.81(t, J=5.3 Hz, 2H), 2.91 (s, 5H), 3.17 (m, 3H), 3.43 (m, 2H), 3.56 (t,J=5.6 Hz, 2H), 4.13 (m, 1H), 4.32 (s, 2H), 4.80 (m, 1H), 7.34 (m, 1H),7.54 (t, J=10.9 Hz, 2H); ESI-MS m/z [M+H]⁺ 482.5.

EXAMPLE 133-fluoro-4-((1-(3-(isopropylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile

A solution of3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (12.8 mg, 0.024 mmol) and formaldehyde (2.2 mg, 0.027 mmol) inMeOH (244 μL) at room temperature was treated with DIPEA (8.5 μL, 0.049mmol) and sodium triacetoxyhydroborate (10.3 mg, 0.049 mmol). Thereaction mixture was stirred for 45 min at room temperature. The crudereaction mixture was purified directly by HPLC Method B, with theexception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used,using a 30% to 55% ACN gradient to give the title compound (about 90%purity), as a TFA salt, as a pale yellow solid. (6.0 mg, 46%). ¹H NMR(400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.98 (m, 2H), 2.19(m, 2H), 3.08 (m, 7H), 3.38 (m, 3H), 3.76 (br s, 1H), 4.16 (m, 1H), 4.29(m, 2H), 4.79 (m, 1H), 7.34 (m, 1H), 7.53 (m, 2H); ESI-MS m/z [M+H]⁺425.5.

EXAMPLE 14(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(morpholino)methanone

To a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (38.1 mg, 0.074 mmol) in DCM (736 μL) at 0° C. was addedtriethylamine (30.8 μL, 0.221 mmol), followed by morpholine-4-carbonylchloride (17.2 μL, 0.147 mmol). The reaction mixture was allowed to warmto room temperature and was stirred for 30 min. The reaction mixture wasconcentrated under reduced pressure and purified directly by HPLC MethodB, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mmcolumn was used, using a 50% to 75% ACN gradient to give the titlecompound, as a TFA salt, as a yellow solid (11.9 mg, 25.6%). ¹H NMR (400MHz, methanol-d4) δ ppm 1.31 (d, J=6.6 Hz, 6H), 1.96 (m, 2H), 2.13 (m,2H), 2.81 (t, J=5.8 Hz, 2H), 3.10 (m, 2H), 3.33 (m, 4H), 3.45 (m, 2H),3.59 (t, J=5.9 Hz, 2H), 3.70 (m, 4H), 4.13 (m, 1H), 4.37 (s, 2H), 4.50(tt, J=7.2, 3.5 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz,1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 517.5.

EXAMPLE 153-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N-(2-methoxyethyl)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

To a solution of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (42.8 mg, 0.070 mmol) and triethylamine (0.029 mL, 0.211 mmol)in DCM (0.75 mL) was added 1-isocyanato-2-methoxyethane (11.0 μL, 0.105mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min andthen concentrated via rotary evaporation. The crude material was dilutedwith DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B,with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mmwas used, using an ACN gradient of 30% to 70% to give the title compoundas a TFA salt (26.3 mg, 60.5%) as a hygroscopic, yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.18 (d, J=6.3 Hz, 6H), 1.83-1.93 (m, 2H),2.02-2.11 (m, 2H), 2.61 (t, J=5.6 Hz, 2H), 2.82-2.93 (m, 2H), 3.14-3.21(m, 2H), 3.23 (s, 3H), 3.24-3.31 (m, 2H), 3.31-3.37 (m, 2H), 3.60 (t,J=5.8 Hz, 2H), 4.08-4.17 (m, 1H), 4.29 (s, 2H), 4.49-4.56 (m, 1H),5.61-5.70 (m, 1H), 6.66-6.73 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.34 (m,2H); ESI-MS m/z [M+H]⁺ 505.0.

EXAMPLE 16(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(tetrahydrofuran-2-yl)methanone

To a suspension of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (42.8 mg, 0.070 mmol), 2-tetrahydrofuroic acid (10.1 μL, 0.105mmol), HATU (40.0 mg, 0.105 mmol) in DMA (0.75 mL) was added DIPEA(0.037 mL, 0.211 mmol) at 23° C. The mixture was stirred at 60° C. for30 min, cooled to 23° C., filtered, rinsed with DMSO, and purified byHPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm,ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give thetitle compound as a TFA salt (20.8 mg, 48.1%) as a hygroscopic, yellowsolid. ¹H NMR (400 MHz, DMSO-d₆, mixture of rotamers) δ ppm 1.19 (d,J=6.3 Hz, 6H), 1.78-1.94 (m, 4H), 1.97-2.13 (m, 4H), 2.63 (t, J=5.7 Hz,0.9H), 2.71-2.77 (m, 1.1H), 2.85-2.95 (m, 2H), 3.24-3.33 (m, 2H),3.69-3.85 (m, 4H), 4.11 (dt, J=12.9, 6.4 Hz, 1H), 4.38-4.57 (m, 3H),4.75 (ddd, J=14.0, 7.8, 5.7 Hz, 1H), 5.81 (br s, 1H), 6.99-7.05 (m, 1H),7.25-7.34 (m, 2H); ESI-MS m/z [M+H]⁺ 502.5.

EXAMPLE 173-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-3-oxopropanenitrile

To a suspension of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (42.8 mg, 0.070 mmol), cyanoacetic acid (9.0 mg, 0.105 mmol),HATU (40.0 mg, 0.105 mmol) in DMA was added DIPEA (36.7 μL, 0.211 mmol)at 23° C. The mixture was stirred at 60° C. for 30 min, cooled to 23°C., filtered, rinsed with DMSO, and purified by HPLC Method B, with theexception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used,using an ACN gradient of 30% to 70% to give the title compound as a TFAsalt (21.0 mg, 51.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆,mixture of rotamers) δ ppm 1.19 (d, J=6.6 Hz, 6H), 1.80-1.96 (m, 2H),2.00-2.17 (m, 2H), 2.64 (t, J=5.6 Hz, 0.9H), 2.76 (t, J=5.7 Hz, 1.1H),2.84-2.97 (m, 2H), 3.22-3.34 (m, 2H), 3.64 (t, J=5.8 Hz, 1.1H), 3.75 (t,J=5.9 Hz, 0.9H), 4.08-4.14 (m, 1H), 4.16 (s, 0.9H), 4.17 (s, 1.1H), 4.37(s, 0.9H), 4.43 (s, 1.1H), 4.48-4.57 (m, 1H), 5.76 (br s, 1H), 6.98-7.06(m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]⁺ 471.5.

EXAMPLE 18(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(isoxazol-5-yl)methanone

A solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (38.1 mg, 0.074 mmol) in DCM (736 μL) at 0° C. was treated withtriethylamine (30.8 μL, 0.221 mmol), followed by isoxazole-5-carbonylchloride (14.2 μL, 0.147 mmol). The reaction mixture was allowed to warmto room temperature and stir for 45 min. The reaction mixture wasconcentrated under reduced pressure and purified directly by HPLC MethodB, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mmcolumn was used, using a 55% to 90% ACN gradient to give the titlecompound, as a TFA salt, as a tan oil (18.6 mg, 41.2%). ¹H NMR (400 MHz,methanol-d4) δ ppm 1.30 (m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.89 (m,2H), 3.11 (m, 2H), 3.46 (m, 2H), 3.91-4.21 (m, 3H), 4.49 (m, 1H), 4.78(br s, 2H), 6.87 (m, 1H), 6.92 (s, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz,1H), 7.17 (td, J=9.2, 5.6 Hz, 1H), 8.55 (s, 1H); ESI-MS m/z [M+H]⁺499.5.

EXAMPLE 194-((1-(6-acetyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile

To a solution of3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol)in DCM (1.0 mL) was added acetyl chloride (0.013 mL, 0.188 mmol) at 0°C. The reaction mixture was stirred at 0° C. for 30 min and thenconcentrated via rotary evaporation. The crude material was diluted withDMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, withthe exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm wasused, using an ACN gradient of 30% to 70% to give the title compound asa TFA salt (8.7 mg, 16%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆,mixture of rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.86-1.96 (m, 2H),2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.10-2.21 (m, 2H), 2.61 (t, J=5.6 Hz,0.9H), 2.73 (t, J=5.2 Hz, 1.1H), 2.88-2.98 (m, 2H), 3.23-3.31 (m, 2H),3.66-3.76 (m, 2H), 4.09-4.17 (m, 1H), 4.40 (s, 1.1H), 4.43 (s, 0.9H)4.80-4.87 (m, 1H), 5.59-5.67 (m, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.68 (dq,J=8.6, 1.7 Hz, 1H), 7.86 (dt, J=11.2, 1.7 Hz, 1H); ESI-MS m/z [M+H]⁺453.5.

EXAMPLE 204-((1-(6-(cyclopropanecarbonyl)-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile

To a solution of3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol)in DCM (0.5 mL) was added cyclopropanecarboxylic acid chloride (0.017mL, 0.188 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min andthen concentrated via rotary evaporation. The crude material was dilutedwith DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B,with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mmwas used, using an ACN gradient of 30% to 70% to give the title compoundas a TFA salt (8.1 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆,mixture of rotamers) δ ppm 0.69-0.79 (m, 4H), 1.18 (d, J=6.6 Hz, 6H),1.91 (dd, J=19.5, 5.6 Hz, 2H), 2.13 (dd, J=14.3, 6.2 Hz, 2H), 2.52-2.53(m, 1H), 2.57-2.64 (m, 0.9H), 2.75 (t, J=6.2 Hz, 1.1H), 2.88-2.99 (m,2H), 3.22-3.31 (m, 2H), 3.72-3.77 (m, 0.9H), 3.95 (t, J=5.8 Hz, 1H),4.10-4.16 (m, 1H), 4.42 (br s, 1.1H), 4.67 (br s, 0.9H), 4.80-4.87 (m,1H), 5.61-5.67 (m, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.65-7.70 (m, 1H), 7.86(dd, J=11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]⁺ 479.5.

EXAMPLE 212-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-6-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (47 mg, 0.091 mmol) in DCM (908 μL) at 0° C. was treated withtriethylamine (38.0 μL, 0.272 mmol), followed by propane-2-sulfonylchloride (15.3 μL, 0.136 mmol). The reaction mixture was allowed to stirfor 45 min, gradually warming to room temperature. The reaction mixturewas concentrated under reduced pressure and was purified by HPLC MethodB, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mmcolumn was used, using a 60% to 95% ACN gradient to give the titlecompound, as a TFA salt, as a yellow oil (16.4 mg, 29.0%). ¹H NMR (400MHz, methanol-d4) δ ppm 1.29 (d, J=6.6 Hz, 6H), 1.35 (d, J=6.8 Hz, 6H),1.95 (m, 2H), 2.13 (m, 2H), 2.82 (t, J=5.9 Hz, 2H), 3.07 (m, 2H), 3.42(m, 3H), 3.67 (t, J=5.8 Hz, 2H), 4.12 (septet, J=6.5 Hz, 1H), 4.41 (s,2H), 4.48 (dt, J=7.5, 3.6 Hz, 1H) 6.87 (m, 1H), 6.98 (ddd, J=11.3, 8.5,2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 510.5.

EXAMPLE 222-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-6-(methyl-L-prolyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine

A solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16.8 mg, 0.130mmol) in DMA (0.4 mL) was treated with HATU (49.6 mg, 0.130 mmol) andDIPEA (45.6 μL, 0.261 mmol) at room temperature. To this was added asolution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (45 mg, 0.087 mmol) in DMA (0.47 mL). The reaction mixture wasstirred at 60° C. for 45 min. The reaction mixture was allowed to coolto room temperature and was purified directly directly by HPLC Method B,with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mmcolumn was used, using a 25% to 60% ACN gradient to give the titlecompound, as a TFA salt, as a white solid (2.8 mg, 5.1%). ¹H NMR (400MHz, methanol-d4) δ ppm 1.26 (dd, J=6.6, 4.5 Hz, 6H), 1.97 (m, 4H), 2.09(m, 3H), 2.24 (m, 1H), 2.76 (m, 3H), 2.93 (app d, J=7.6 Hz, 3H), 3.03(m, 2H), 3.20 (m, 1H), 3.40 (m, 2H), 3.69-4.19 (m, 4H), 4.48 (m, 2H),4.66 (m, 2H), 6.87 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17(td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 515.6.

EXAMPLE 23(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(pyrrolidin-1-yl)methanone

A solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (45 mg, 0.087 mmol) in DCM (870 μL) at 0° C. was treated withtriethylamine (36.4 μL, 0.261 mmol), followed by pyrrolidine-1-carbonylchloride (19.2 μL, 0.174 mmol). The reaction mixture was allowed to stirfor 30 min, gradually warming to room temperature. The reaction mixturewas concentrated under reduced pressure and purified directly by HPLCMethod B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID30×75 mm column was used, using a 50% to 80% ACN gradient to give thetitle compound, as a TFA salt, as a pale yellow solid (10.6 mg, 19.8%).¹H NMR (400 MHz, methanol-d4) δ ppm 1.33 (d, J=6.3 Hz, 6H), 1.89 (m,4H), 1.97 (m, 2H), 2.14 (m, 2H), 2.81 (t, J=5.8 Hz, 2H), 3.13 (m, 2H),3.46 (m, 6H), 3.61 (t, J=5.8 Hz, 2H), 4.12 (septet, J=6.4 Hz, 1H), 4.38(s, 2H), 4.51 (tt, J=7.2, 3.6 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J=11.4,8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 501.6.

EXAMPLE 241-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethan-1-one

A solution of 2,2-difluoroacetic acid (8.2 μL, 0.13 mmol) in DMA (0.4mL) was treated with HATU (49.6 mg, 0.130 mmol) and DIPEA (45.6 μL,0.261 mmol). To this was added a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (45 mg, 0.087 mmol) in DMA (0.47 mL). The reaction mixture washeated at 60° C. for 50 min. The reaction mixture was allowed to cool toroom temperature and was purified directly by HPLC Method B, with theexception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column wasused, using a 55% to 90% ACN gradient to give the title compound, as aTFA salt, as a yellow solid (10.0 mg, 19.3%). ¹H NMR (400 MHz,methanol-d4, mixture of rotamers) δ ppm 1.28 (m, 6H), 1.96 (m, 2H), 2.12(m, 2H), 2.79 (t, J=5.9 Hz, 0.7H), 2.85 (t, J=5.8 Hz, 1.3H), 3.05 (m,2H), 3.42 (m, 2H), 3.92 (dt, J=11.3, 5.8 Hz, 2H), 4.15 (m, 1H), 4.48 (m,1H), 4.65 (s, 2H), 6.56 (m, 1H), 6.88 (m, 1H), 6.98 (ddd, J=11.3, 8.5,2.9 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 482.5.

EXAMPLE 253-fluoro-4-((1-(2-(isopropylamino)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile

To a solution of3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol)in DCM (1.0 mL) was added methanesulfonyl chloride (10.9 μL, 0.141 mmol)at 0° C. The mixture was stirred at 0° C. for 30 min and thenconcentrated via rotary evaporation. The crude material was diluted withDMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, withthe exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm wasused, using an ACN gradient of 30% to 70% to give the title compound asa TFA salt (3.5 mg, 6.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.18 (d, J=6.3 Hz, 6H), 1.88-1.96 (m, 2H), 2.09-2.16 (m, 2H), 2.76(t, J=5.9 Hz, 2H), 2.89-2.96 (m, 2H), 2.97 (s, 3H), 3.24-3.30 (m, 2H),3.45 (t, J=5.9 Hz, 2H), 4.10-4.16 (m, 3H), 4.81-4.85 (m, 1H), 5.66 (d,J=8.3 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.68 (ddd, J=8.6, 2.0, 1.3 Hz,1H), 7.86 (dd, J=11.4, 2.0 Hz, 1H); ESI-MS m/z [M+H]⁺ 489.5.

EXAMPLE 263-fluoro-4-((1-(2-(isopropylamino)-6-(2-methoxyacetyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile

To a solution of3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile2,2,2-trifluoroacetate (98.6 mg, 0.094 mmol) and triethylamine (0.039mL, 0.283 mmol) in DCM (1.0 mL) was added methoxyacetyl chloride (0.017mL, 0.188 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min andthen concentrated via rotary evaporation. The crude material was dilutedwith DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B,with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mmwas used, using an ACN gradient of 30% to 70% to give the title compoundas a TFA salt (2.9 mg, 5.2%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆, mixture of rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.87-1.97(m, 2H), 2.08-2.16 (m, 2H), 2.62 (t, J=5.8 Hz, 0.9H), 2.72 (t, J=6.1 Hz,1.1H), 2.89-2.97 (m, 2H), 3.22-3.28 (m, 1H), 3.29 (br s, 1.3H), 3.30 (s,1.7H), 3.64-3.67 (m, 1.1H), 3.72-3.75 (m, 0.9H), 4.10-4.16 (m, 1H), 4.17(br s, 0.9H), 4.19 (s, 1.1H), 4.36 (br s, 0.9H), 4.41 (s, 1.1H),4.80-4.86 (m, 1H), 5.58-5.63 (m, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.66-7.70(m, 1H), 7.87 (dd, J=11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]⁺ 483.5.

EXAMPLE 273-fluoro-4-((1-(2-(isopropylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile

To a solution of3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (20.7 mg, 0.039 mmol) and formaldehyde (3.2 μL, 0.043 mmol) inMeOH (0.5 mL) was added DIPEA (0.014 mL, 0.079 mmol) and sodiumtriacetoxyborohydride (16.7 mg, 0.079 mmol) at 23° C. The mixture wasstirred at 23° C. for 2 hr and then concentrated via rotary evaporation.The crude material was diluted with DMSO, filtered, rinsed with DMSO,and purified by with the exception that a Waters XSelect® CSH C18, 5 μm,ID 4.6×50 mm was used, using a 30% to 40% ACN gradient to give the titlecompound as a TFA salt (5.3 mg, 25%) as a light yellow solid. ¹H NMR(400 MHz, DMSO-d₆, mixture of rotamers) δ ppm 1.16-1.24 (m, 6H),1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H), 2.74-2.85 (m, 0.9H), 2.85-2.92 (m,1.1H), 2.95 (br s, 1.3H), 2.96 br s, 1.7H), 2.97-3.00 (m, 1H), 3.25-3.42(m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m, 2H), 4.25-4.31 (m, 1H),4.82-4.88 (m, 1H), 5.89 (d, J=8.3 Hz, 1H), 7.50 (t, J=8.6 Hz, 1H),7.66-7.71 (m, 1H), 7.87 (dd, J=11.4, 2.0 Hz, 1H), 9.96 (br s, 1H);ESI-MS m/z [M+H]⁺ 425.5.

EXAMPLE 283-(4-(4-cyano-2-fluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

To a solution of3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrileTFA salt (20.7 mg, 0.039 mmol) and triethylamine (0.017 mL, 0.118 mmol)in DCM (0.5 mL) was added dimethylcarbamoyl chloride (7.3 μL, 0.079mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and thenconcentrated via rotary evaporation. The crude material was diluted withDMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, withthe exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm wasused, using a 30% to 70% ACN gradient to give the title compound as aTFA salt (11.6 mg, 49.4%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.13-1.26 (m, 6H), 1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H),2.81-2.99 (m, 6H), 3.25-3.42 (m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m,2H), 4.25-4.31 (m, 1H), 4.82-4.88 (m, 1H), 5.89 (d, J=8.3 Hz, 1H), 7.50(t, J=8.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.87 (dd, J=11.4, 2.0 Hz, 1H),9.96 (br s, 1H); ESI-MS m/z [M+H]⁺ 482.5.

EXAMPLE 291-(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

A solution ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.027 mmol), DIPEA (14.20 μL, 0.081 mmol), and aceticanhydride (3.8 μL, 0.041 mmol) in DCM (271 μL) was stirred at roomtemperature overnight. Purification by HPLC Method A gave the titlecompound as a TFA salt (8.9 mg) as an off-white film. ¹H NMR (500 MHz,methanol-d4, mixture of rotamers) δ ppm 1.45 (d, J=6.8 Hz, 1.9H), 1.58(d, J=6.8 Hz, 1.1H), 1.93-2.02 (m, 2H), 2.14 (dd, J=12.7, 3.4 Hz, 2H),2.19-2.23 (m, 3H), 2.62-2.83 (m, 1.5H), 2.87-3.08 (m, 3.2H), 3.35-3.43(m, 2H), 3.48-3.55 (m, 0.7H), 3.78 (sxtd, J=14.4, 4.2 Hz, 2H), 4.06 (dd,J=14.2, 5.4 Hz, 0.6H), 4.46 (dt, J=7.6, 3.5, Hz, 1H), 4.73 (dd, J=13.2,5.4 Hz, 0.4H), 5.34 (q, J=6.8 Hz, 0.6H), 5.92-5.97 (m, 1H), 6.06 (dt,J=9.0, 4.3, Hz, 1H), 6.15-6.20 (m, 1H), 6.86-6.91 (m, 1H), 6.99 (ddd,J=11.2, 8.5, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z[M+H]⁺ 482.

EXAMPLE 30N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.027 mmol), DIPEA (14.2 μL, 0.081 mmol), andmethanesulfonyl chloride (3.2 μL, 0.041 mmol) in DCM (271 μL) wasstirred overnight. Purification by HPLC Method A gave the title compoundas a TFA salt (6.4 mg) as a white film. ¹H NMR (500 MHz, methanol-d4) δppm 1.54 (d, J=6.8 Hz, 3H), 1.91-2.02 (m, 2H), 2.07-2.19 (m, 2H), 2.66(dd, J=16.8, 3.2 Hz, 1H), 2.91 (s, 3H), 2.93-3.06 (m, 3H), 3.34-3.48 (m,3H), 3.68-3.88 (m, 2H), 3.98 (dd, J=14.2, 6.4 Hz, 1H), 4.45 (dt, J=7.4,3.8, Hz, 1H), 4.77 (q, J=6.8 Hz, 1H), 5.87-6.21 (m, 1H), 6.82-6.92 (m,1H), 6.98 (ddd, J=11.4, 8.7, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 518.80.

EXAMPLE 311-(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethanone

A solution of 2-methoxyacetic acid (2.4 mg, 0.027 mmol), HATU (10.3 mg,0.027 mmol), and DIPEA (14.2 μL, 0.081 mmol) in DMF (271 p.1) wasstirred at room temperature for 10 min. To this was then addedN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.027 mmol) in DCM (271 μL) and the reaction mixturewas stirred overnight. Purification by HPLC Method A afforded the titlecompound as a TFA salt (7.4 mg) as an off-white film. ¹H NMR (500 MHz,methanol-d4, mixture of rotamers) δ ppm 1.47 (d, J=6.8 Hz, 2H), 1.58 (d,J=6.8 Hz, 1H), 1.93-2.03 (m, 2H), 2.10-2.18 (m, 2H), 2.63-3.06 (m,4.1H), 3.12 (td, J=12.9, 3.9 Hz, 0.3H), 3.36-3.51 (m, 5.6H), 3.70-3.88(m, 2H), 4.02 (dd, J=13.9, 5.6 Hz, 0.7H), 4.18-4.33 (m, 2H), 4.46 (dt,J=7.3, 3.7 Hz, 1H), 4.71 (dd, J=13.4, 5.6 Hz, 0.3H), 4.79-4.84 (m,0.3H), 5.30 (q, J=6.8 Hz, 0.7H), 5.91-6.21 (m, 1H), 6.85-6.92 (m, 1H),6.99 (ddd, J=11.3, 8.7, 2.9 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 512.85.

EXAMPLE 321-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared as an off-white film in a manner similarto Example 29 usingN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.43 (d, J=6.8Hz, 1.8H), 1.56 (d, J=6.8 Hz, 1.2H), 1.95-2.03 (m, 2H), 2.10-2.23 (m,5H), 2.63-2.83 (m, 1.6H), 2.88-3.10 (m, 3.2H), 3.35-3.47 (m, 2H),3.48-3.57 (m, 0.5H), 3.78 (td, J=14.4, 4.4 Hz, 2H), 4.05 (dd, J=13.9,5.6 Hz, 0.6H), 4.42-4.51 (m, 1H), 4.73 (dd, J=13.7, 5.9 Hz, 0.6H), 5.35(q, J=6.7 Hz, 0.5H), 5.92-6.20 (m, 1H), 6.84-6.93 (m, 1H), 6.96-7.04 (m,1H), 7.14-7.23 (m, 1H); ESI-MS m/z [M+H]⁺ 482.

EXAMPLE 33N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

The title compound was prepared as a white film in a manner similar toExample 30 usingN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine¹H NMR (500 MHz, methanol-d4) δ ppm 1.52 (d, J=6.8 Hz, 3H), 1.91-2.01(m, 2H), 2.08-2.19 (m, 2H), 2.66 (dd, J=17.1, 2.9 Hz, 1H), 2.91 (s, 3H),2.93-3.08 (m, 3H), 3.34-3.48 (m, 3H), 3.77 (td, J=14.4, 4.4 Hz, 2H),3.97 (dd, J=14.2, 6.4 Hz, 1H), 4.40-4.51 (m, 1H), 4.78 (q, J=6.7 Hz,1H), 5.88-6.21 (m, 1H), 6.82-6.92 (m, 1H), 6.98 (ddd, J=11.2, 8.3, 2.9Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 518.80.

EXAMPLE 341-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethanone

The title compound was prepared as an off-white film in a manner similarto Example 31 usingN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.45 (d, J=6.8Hz, 2H), 1.56 (d, J=6.8 Hz, 1H), 1.93-2.02 (m, 2H), 2.11-2.18 (m, 2H),2.63-3.18 (m, 4.5H), 3.35-3.51 (m, 5.5H), 3.78 (td, J=14.5, 4.1 Hz, 2H),4.01 (dd, J=13.7, 5.4 Hz, 0.7H), 4.19-4.33 (m, 2H), 4.47 (dd, J=7.3, 3.9Hz, 1H), 4.70 (dd, J=13.2, 5.9 Hz, 0.3H), 4.80-4.84 (m, 0.3H), 5.31 (q,J=6.7 Hz, 0.7H), 5.93-6.20 (m, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd,J=11.3, 8.7, 2.9 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z[M+H]⁺ 512.80.

EXAMPLE 351-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared as a light yellow film in a mannersimilar to Example 29 using3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm1.30-1.36 (m, 6H), 1.45 (d, J=6.8 Hz, 1.8H), 1.58 (d, J=6.8 Hz, 1.2H),1.98 (d, J=6.8 Hz, 2H), 2.15 (dd, J=8.5, 4.6 Hz, 2H), 2.19-2.23 (m, 3H),2.70-2.85 (m, 1.4H), 2.91-3.17 (m, 3.3H), 3.44-3.57 (m, 2.7H), 4.06-4.19(m, 1.6H), 4.48-4.55 (m, 1H), 4.76 (dd, J=13.7, 5.4 Hz, 0.4H), 5.35 (q,J=6.8 Hz, 0.6H), 6.86-6.92 (m, 1H), 7.00 (ddd, J=11.3, 8.7, 2.9 Hz, 1H),7.19 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 460.2.

EXAMPLE 363-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

The title compound was prepared as an off-white film in a manner similarto Example 30 using3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4) δ ppm 1.25-1.31 (m, 6H), 1.52(d, J=6.4 Hz, 3H), 1.90-2.02 (m, 2H), 2.09-2.19 (m, 2H), 2.70 (dd,J=17.3, 3.2 Hz, 1H), 2.88-3.13 (m, 6H), 3.37-3.50 (m, 3H), 3.98 (dd,J=14.2, 6.4 Hz, 1H), 4.15 (dt, J=13.1, 6.4 Hz, 1H), 4.48 (dt, J=7.4, 3.8Hz, 1H), 4.77 (q, J=7.0 Hz, 1H), 6.84-6.92 (m, 1H), 6.99 (ddd, J=11.4,8.7, 2.9 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺496.90.

EXAMPLE 371-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethanone

The title compound was prepared as an off-white film in a manner similarto Example 31 usingN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.29-1.37 (m,6H), 1.47 (d, J=6.8 Hz, 2H), 1.58 (d, J=6.8 Hz, 1H), 1.98 (d, J=9.8 Hz,2H), 2.14 (br s, 2H), 2.72-2.88 (m, 1.5H), 2.92-3.00 (m, 0.8H),3.09-3.17 (m, 2.5H), 3.41-3.53 (m, 5.7H), 4.06 (dd, J=14.2, 5.4 Hz,0.8H), 4.10-4.33 (m, 3.2H), 4.52 (d, J=3.4 Hz, 1H), 4.72 (dd, J=13.4,5.6 Hz, 0.4H), 4.80-4.84 (m, 0.4H), 5.31 (q, J=6.3 Hz, 0.7H), 6.89 (t,J=8.5 Hz, 1H), 7.00 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.19 (td, J=9.3, 5.4Hz, 1H); ESI-MS m/z [M+H]⁺ 490.95.

EXAMPLE 38Cyclopropyl(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone

The title compound was prepared as an off-white film in a manner similarto Example 31 usingN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt. ¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm0.81-1.05 (m, 4H), 1.45 (d, J=6.8 Hz, 1.6H), 1.64 (d, J=6.8 Hz, 1.4H),1.94-2.18 (m, 5.4H), 2.61-2.83 (m, 1.6H), 2.89-3.12 (m, 3.2H), 3.35-3.44(m, 2.1H), 3.51-3.60 (m, 0.6H), 3.71-3.86 (m, 2H), 4.42-4.51 (m, 1.6H),4.70 (dd, J=13.2, 4.9 Hz, 0.5H), 5.21-5.37 (m, 1H), 5.91-6.20 (m, 1H),6.85-6.91 (m, 1H), 6.99 (ddd, J=11.3, 8.7, 2.9 Hz, 1H), 7.18 (td, J=9.3,5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 508.85.

EXAMPLE 39Cyclopropyl(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone

The title compound was prepared as a white film in a manner similar toExample 31 usingN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm0.80-1.06 (m, 4H), 1.43 (d, J=6.8 Hz, 1.5H), 1.62 (d, J=6.8 Hz, 1.5H),1.91-2.20 (m, 5.5H), 2.62-2.83 (m, 1.6H), 2.90-3.13 (m, 3.2H), 3.35-3.48(m, 2.1H), 3.52-3.61 (m, 0.5H), 3.78 (td, J=14.4, 3.9 Hz, 2H), 4.46 (dd,J=8.3, 4.4 Hz, 1.6H), 4.69 (dd, J=13.2, 4.9 Hz, 0.5H), 5.21-5.38 (m,1H), 5.92-6.20 (m, 1H), 6.88 (t, J=8.5 Hz, 1H), 6.96-7.03 (m, 1H), 7.18(td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 508.85.

EXAMPLE 40Cyclopropyl(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone

The title compound was prepared as a light yellow film in a mannersimilar to Example 31 using3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm0.79-1.05 (m, 4H), 1.30 (t, J=6.3 Hz, 6H), 1.44 (d, J=6.8 Hz, 1.5H),1.63 (d, J=6.8 Hz, 1.5H), 1.92-2.18 (m, 5.1H), 2.67-2.84 (m, 1.5H),2.91-3.13 (m, 3H), 3.44 (td, J=7.9, 3.7 Hz, 2H), 3.53-3.61 (m, 0.5H),4.16 (dt, J=11.8, 6.0 Hz, 1H), 4.49 (d, J=7.3 Hz, 1.5H), 4.70 (dd,J=12.9, 5.1 Hz, 0.4H), 5.21-5.37 (m, 1H), 6.89 (t, J=8.3 Hz, 1H),6.96-7.04 (m, 1H), 7.19 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺486.90.

EXAMPLE 411-(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

A solution of 2,2-difluoroacetic acid (2.86 mg, 0.030 mmol), HATU (11.3mg, 0.030 mmol), and DIPEA (14.2 μL, 0.081 mmol) in DMF (136 μL) wasstirred at room temperature for 10 min. Then,N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.027 mmol) was added and stirring was continuedovernight. No desired product was detected by LCMS. To this was added2,2-difluoroacetic anhydride (7.08 mg, 0.041 mmol) and after 1 h,purification by HPLC Method A afforded the title compound as a TFA salt(4.4 mg) as an off-white film. ¹H NMR (500 MHz, methanol-d4, mixture ofrotamers) δ ppm 1.51 (d, J=6.8 Hz, 2.1H), 1.62 (d, J=6.8 Hz, 0.9H),1.94-2.02 (m, 2H), 2.10-2.18 (m, 2H), 2.68-2.78 (m, 1H), 2.82-3.06 (m,3.2H), 3.36-3.44 (m, 2H), 3.53-3.61 (m, 0.7H), 3.71-3.88 (m, 2.1H), 4.16(dd, J=14.2, 5.4 Hz, 0.7H), 4.46 (dt, J=7.4, 3.8 Hz, 1H), 4.67 (dd,J=13.2, 5.9 Hz, 0.3H), 4.97 (q, J=6.7 Hz, 0.3H), 5.27 (q, J=6.8 Hz,0.7H), 5.93-6.20 (m, 1H), 6.43-6.70 (m, 1H), 6.85-6.92 (m, 1H), 6.99(ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z[M+H]⁺ 518.80.

EXAMPLE 421-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

The title compound was prepared as an off-white film in a manner similarto Example 41 usingN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.50(d, J=6.8 Hz, 2.1H), 1.60 (d, J=6.8 Hz, 0.9H), 1.92-2.03 (m, 2H),2.11-2.18 (m, 2H), 2.68-2.77 (m, 1H), 2.82-3.08 (m, 3H), 3.26 (td,J=12.9, 12.9, 3.9 Hz, 0.4H), 3.36-3.47 (m, 2H), 3.53-3.62 (m, 0.6H),3.78 (td, J=14.4, 4.4 Hz, 2H), 4.15 (dd, J=13.9, 5.6 Hz, 0.7H),4.43-4.49 (m, 1H), 4.66 (dd, J=13.2, 5.9 Hz, 0.3H), 4.98 (q, J=6.8 Hz,0.3H), 5.28 (q, J=6.8 Hz, 0.7H), 5.93-6.19 (m, 1H), 6.43-6.69 (m, 1H),6.86-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J=9.2,5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 518.85.

EXAMPLE 431-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

The title compound was prepared as an off-white film in a manner similarto Example 41 using3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm1.25-1.30 (m, 6H), 1.49 (d, J=6.8 Hz, 2H), 1.60 (d, J=6.3 Hz, 1H),1.91-2.01 (m, 2H), 2.10-2.18 (m, 2H), 2.70-2.80 (m, 1H), 2.81-3.09 (m,3H), 3.22-3.30 (m, 0.5H), 3.37-3.47 (m, 2H), 3.54-3.62 (m, 0.6H),4.12-4.21 (m, 1.6H), 4.45-4.52 (m, 1H), 4.66 (dd, J=13.4, 6.1 Hz, 0.3H),4.93-4.99 (m, 0.3H), 5.26 (q, J=6.5 Hz, 0.7H), 6.43-6.69 (m, 1H),6.86-6.92 (m, 1H), 7.00 (ddd, J=11.3, 8.7, 2.9 Hz, 1H), 7.19 (td, J=9.3,5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 496.90.

EXAMPLE 441-(3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

Acetic anhydride (9 μL, 0.095 mmol) was added to a solution of3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (25.2 mg, 0.048 mmol) and pyridine (11.5 μL, 0.143 mmol) in DCM(500 μL) at rt. After 1 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (25.2 mg, 93%) as a yellow film.¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.32 (d, J=6.6Hz, 6H), 1.89-2.00 (m, 2H), 2.06-2.15 (m, 2H), 2.19 (s, 1.4H), 2.21 (s,1.6H), 2.77-2.83 (m, 0.9H), 2.87-2.93 (m, 1.1H), 3.04-3.14 (m, 2H),3.42-3.50 (m, 2H), 3.75 (s, 3H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m,0.9H), 4.09-4.19 (m, 1H), 4.35-4.42 (m, 1H), 4.55 (br s, 2H), 6.67 (dt,J=9.0, 1.4 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz,1H); ESI-MS m/z [M+H]⁺ 458.4.

EXAMPLE 451-(2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to Example 29 using2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt. ESI-MS m/z [M+H]⁺ 458.40.

EXAMPLE 462-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-3-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (4.9 mg, 0.046 mmol) was added to a solutionof2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (12.1 mg, 0.023 mmol) and triethylamine (10 μL, 0.069 mmol) inDCM (230 μL) at rt. After 1 h, the mixture was purified by HPLC Method Ato give the title compound as a TFA salt (12.1 mg, 88%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.27-1.32 (m, 6H), 1.89-1.99(m, 2H), 2.06-2.15 (m, 2H), 2.81 (s, 2H), 2.91 (s, 6H), 3.00-3.09 (m,2H), 3.39-3.46 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.75 (s, 3H), 4.13(quin, J=6.4 Hz, 1H), 4.30 (s, 2H), 4.34-4.40 (m, 1H), 6.67 (ddd, J=8.9,3.0, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H);ESI-MS m/z [M+H]⁺ 487.4.

EXAMPLE 471-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

A mixture of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine(100 mg, 0.250 mmol), acetic anhydride (0.09 mL, 1.00 mmol) and 10% Pd/C(9.0 mg) in a mixture of dioxane (2.5 mL) and acetone (1.5 mL) wasstirred at room temperature for 24 h. Then, 4.0 equivalents of aceticanhydride was added and stirring was continued for 2 days. Afterfiltration, the reaction solution was quenched with saturated NaHCO₃ andthe aqueous layer was extracted with ethyl acetate (3×5 mL). Thecombined organic phase was dried with anhydrous Na₂SO₄ and concentratedunder vacuum. Purification by silica gel column chromatography using a30% to 100% gradient of EtOAc in heptane gave the title compound (57 mg,51%) as a white solid. ¹H NMR (400 MHz, methanol-d₄, mixture ofrotamers) δ ppm 1.23 (d, J=6.6 Hz, 3.3H), 1.24 (d, J=6.6 Hz, 2.7H), 1.93(m, 2H), 2.11 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.71 (t, J=6.1Hz, 0.9H), 2.80 (t, J=6.1 Hz, 1.1H), 2.95 (m, 2H), 3.34 (m, 2H), 3.79(t, J=5.9 Hz, 1.1H), 3.84 (t, J=6.1 Hz, 0.9H), 4.15 (m, 1H), 4.44 (tt,J=7.5, 3.7 Hz, 1H), 4.53 (s, 0.9H), 4.54 (s, 1.1H), 6.86 (m, 1H), 6.97(ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z[M+H]⁺ 446.00.

EXAMPLE 492-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15 mg, 0.028 mmol) in DCM (278 μL) at room temperature wastreated with dimethylcarbamic chloride (3.0 mg, 0.028 mmol) and DIPEA(4.9 μL, 0.028 mmol), and the resulting reaction mixture was stirredovernight. The crude reaction mixture was diluted in DMF, filteredthrough a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), andpurified via HPLC Method A to give the title compound as a TFA salt (7mg) as a white solid. ¹H NMR (400 MHz, methanol-d₄) 6 ppm 1.92-2.02 (m,2H), 2.09-2.18 (m, 2H), 2.81-2.86 (m, 2H), 2.90 (s, 6H), 2.96-3.04 (m,2H), 3.34-3.42 (m, 2H), 3.54 (t, J=5.9 Hz, 2H), 3.74-3.84 (m, 2H), 4.28(s, 2H), 4.46 (tt, J=7.7, 3.9 Hz, 1H), 5.90-6.22 (m, 1H), 6.88 (dddd,J=9.1, 8.1, 3.2, 1.9 Hz, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18(td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 497.4.

EXAMPLE 501-(2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethanone

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (17 mg, 0.032 mmol), DIPEA (12.2 mg, 0.095 mmol), and2-methoxyacetyl chloride (5.1 mg, 0.047 mmol) in DCM (315 μL) wasstirred at room temperature overnight. The crude reaction mixture wasdiluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR), and purified via HPLC Method A to give thetitle compound as a TFA salt (7 mg) as a clear oil. ¹H NMR (400 MHz,methanol-d₄, mixture of rotamers) δ ppm 1.92-2.03 (m, 2H), 2.09-2.18 (m,2H), 2.77 (t, J=5.8 Hz, 0.9H), 2.84 (t, J=5.8 Hz, 1.1H), 2.96-3.04 (m,2H), 3.37 (d, J=10.4 Hz, 2H), 3.41 (s, 1.5H), 3.42 (s, 1.5H), 3.73-3.83(m, 3H), 3.88 (t, J=5.9 Hz, 1H), 4.24 (s, 0.9H), 4.27 (s, 1.1H),4.41-4.49 (m, 1H), 4.50 (s, 0.9H), 4.53 (s, 1.1H), 5.89-6.21 (m, 1H),6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2,5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 498.3.

EXAMPLE 51(R)-1-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-1-one

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (17 mg, 0.032 mmol), DIPEA (12.2 mg, 0.095 mmol), and HATU(13.2 mg, 0.035 mmol) in DMF (158 μL) was stirred for 10 min at rt. Tothis was added (R)-2-methoxypropanoic acid (3.6 mg, 0.035 mmol), and theresulting reaction mixture stirred overnight. The crude reaction mixturewas diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR), and purified via HPLC Method A to give thetitle compound as a TFA salt (6 mg) as a clear oil. ¹H NMR (400 MHz,methanol-d₄, mixture of rotamers) δ ppm 1.32 (d, J=6.8 Hz, 1.3 H), 1.38(d, J=6.6 Hz, 1.7H), 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.78 (t,J=6.2 Hz, 0.9H), 2.86 (m, 1.1H), 2.97-3.06 (m, 2H), 3.33 (s, 3H),3.35-3.43 (m, 2H), 3.79 (td, J=14.5, 4.3 Hz, 2H), 3.85-3.97 (m, 2H),4.36 (dq, J=12.7, 6.5 Hz, 1H), 4.42-4.49 (m, 1H), 4.58 (m, 0.9H), 4.68(m, 1.1H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.5,3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 512.4.

EXAMPLE 521-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared as a yellow film in a manner similar toExample 29 using2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt. ¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm1.24-1.31 (m, 6H), 1.46 (d, J=6.8 Hz, 2H), 1.59 (d, J=6.8 Hz, 1H),1.92-2.00 (m, 2H), 2.09-2.17 (m, 2H), 2.19-2.23 (m, 3H), 2.61-2.82 (m,1.5H), 2.87-2.96 (m, 0.7H), 2.99-3.09 (m, 2.4H), 3.40 (td, J=7.7, 3.7Hz, 2H), 3.49-3.57 (m, 0.6H), 4.06 (dd, J=13.9, 5.6 Hz, 0.6H), 4.13-4.20(m, 1H), 4.48 (td, J=7.2, 3.7 Hz, 1H), 4.73 (dd, J=13.4, 5.6 Hz, 0.4H),4.84 (br s, 0.2H), 5.39 (q, J=6.5 Hz, 0.6H), 6.85-6.91 (m, 1H), 6.99(ddd, J=11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z[M+H]⁺ 460.90.

EXAMPLE 531-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

A solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.028 mmol), 2,2-difluoroacetic anhydride (7.4 mg,0.042 mmol), and DIPEA (10.94 mg, 0.085 mmol) in DCM (141 μL) wasstirred at room temperature for 1 h. Purification by HPLC Method A gavethe title compound as a TFA salt (8.2 mg) as an off-white film. ¹H NMR(500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (dd, J=7.6, 6.6Hz, 6H), 1.51 (d, J=6.8 Hz, 2.1H), 1.62 (d, J=6.8 Hz, 0.9H), 1.90-2.00(m, 2H), 2.09-2.17 (m, 2H), 2.65-2.75 (m, 1H), 2.80-3.03 (m, 3H), 3.25(td, J=12.9, 3.9 Hz, 0.3H), 3.34-3.42 (m, 2H), 3.52-3.61 (m, 0.7H),4.11-4.21 (m, 1.7H), 4.46 (dt, J=7.3, 3.7 Hz, 1H), 4.66 (dd, J=13.4, 5.6Hz, 0.3H), 4.91-4.98 (m, 0.3H), 5.25 (q, J=6.7 Hz, 0.7H), 6.44-6.69 (m,1H), 6.84-6.92 (m, 1H), 6.99 (ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.18 (td,J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 496.90.

EXAMPLE 542-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound was prepared as an off-white film in a manner similarto Example 30 using2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt. ¹H NMR (500 MHz, methanol-d4) δ ppm 1.26 (dd, J=10.7, 6.4 Hz,6H), 1.54 (d, J=6.8 Hz, 3H), 1.88-2.00 (m, 2H), 2.07-2.18 (m, 2H), 2.64(dd, J=16.6, 2.9 Hz, 1H), 2.89-2.92 (m, 4H), 2.94-3.03 (m, 3H),3.34-3.48 (m, 3H), 3.97 (dd, J=14.2, 6.4 Hz, 1H), 4.15 (quin, J=6.5 Hz,1H), 4.46 (dt, J=7.4, 3.8 Hz, 1H), 4.76 (q, J=6.7 Hz, 1H), 6.81-6.92 (m,1H), 6.98 (ddd, J=11.4, 8.4, 3.2 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 496.95.

EXAMPLE 552-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-N,N,5-trimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.028 mmol), dimethylcarbamic chloride (6.1 mg, 0.056mmol), and DIPEA (10.9 mg, 0.085 mmol) in DCM (282 μL) was stirred atroom temperature overnight. Purification by HPLC Method A afforded thetitle compound as a TFA salt (6.1 mg) as an off-white film. ¹H NMR (500MHz, methanol-d4) δ ppm 1.26 (dd, J=9.3, 6.4 Hz, 6H), 1.50 (d, J=6.8 Hz,3H), 1.89-1.98 (m, 2H), 2.12 (dq, J=13.2, 3.6 Hz, 2H), 2.55-2.64 (m,1H), 2.88 (s, 6H), 2.94-3.03 (m, 3H), 3.34-3.41 (m, 3H), 3.72-3.82 (m,1H), 4.14 (quin, J=6.5 Hz, 1H), 4.45 (dt, J=7.4, 3.8 Hz, 1H), 4.67 (q,J=6.8 Hz, 1H), 6.83-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.4, 3.2 Hz, 1H),7.17 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 489.90.

EXAMPLE 563-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N,5-trimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

The title compound was prepared as an light yellow film in a mannersimilar to Example 55 using3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4) δ ppm 1.34 (dd, J=6.4, 5.4 Hz,6H), 1.51 (d, J=6.8 Hz, 3H), 1.91-2.03 (m, 2H), 2.10-2.18 (m, 2H), 2.70(dd, J=17.1, 2.9 Hz, 1H), 2.89 (s, 6H), 3.03 (s, 1H), 3.09-3.19 (m, 2H),3.33-3.39 (m, 1H), 3.43-3.53 (m, 2H), 3.79 (dd, J=14.2, 5.8 Hz, 1H),4.08-4.18 (m, 1H), 4.46-4.57 (m, 1H), 4.62 (d, J=6.8 Hz, 1H), 6.84-6.93(m, 1H), 6.99 (ddd, J=11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz,1H); ESI-MS m/z [M+H]⁺ 489.95.

EXAMPLE 572-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N,5-trimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

The title compound was prepared as an off-white film in a manner similarto Example 55 usingN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (500 MHz, methanol-d4) δ ppm 1.47 (d, J=6.8 Hz, 3H),1.96 (d, J=8.3 Hz, 2H), 2.12 (d, J=3.4 Hz, 2H), 2.64 (s, 1H), 2.88 (s,6H), 2.97 (d, J=11.7 Hz, 3H), 3.34-3.45 (m, 3H), 3.71-3.83 (m, 3H),4.41-4.49 (m, 1H), 4.67 (d, J=6.8 Hz, 1H), 6.05 (s, 1H), 6.87 (s, 1H),6.95-7.02 (m, 1H), 7.13-7.21 (m, 1H); ESI-MS m/z [M+H]⁺ 511.90.

EXAMPLE 583-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

Sodium triacetoxyborohydride (22.3 mg, 0.105 mmol) was added to amixture of DIPEA (18 μL, 0.105 mmol),3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (27.9 mg, 0.053 mmol) and formaldehyde (4 μL, 0.053 mmol) inMeOH (550 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (27.9 mg, 97%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.25 (d, J=6.3 Hz, 6H),1.88-1.98 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.05 (m, 3H), 3.07 (br s,4H), 3.33-3.40 (m, 2H), 3.41-3.69 (m, 2H), 3.75 (s, 3H), 4.15-4.32 (m,3H), 4.32-4.39 (m, 1H), 6.66 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.73 (dd,J=12.8, 2.9 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]⁺ 430.4.

EXAMPLE 591-(3-((2,2-difluoroethyl)amino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

A solution ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (114 mg, 0.211 mmol) in DCM (2.11 mL) at 0° C. was treated withpyridine (0.051 mL, 0.63 mmol) and acetic anhydride (0.040 mL, 0.42mmol). The reaction mixture was stirred for 30 min at 0° C. The reactionmixture was concentrated under reduced pressure. The residue was takenup in MeOH, filtered, and purified by HPLC Method B, using a 40% to 70%ACN gradient to give the title compound, as a TFA salt, as a yellowsolid (39.7 mg, 32.3%). ¹H NMR (500 MHz, methanol-d4, mixture ofrotamers) δ ppm 1.96 (m, 2H), 2.12 (m, 2H), 2.18 (s, 1.3H), 2.20 (s,1.7H), 2.73 (t, J=5.9 Hz, 0.8H), 2.83 (t, J=5.9Hz, 1.2H), 3.01 (m, 2H),3.39 (m, 2H), 3.80 (m, 4H), 4.45 (dt, J=7.0, 3.6 Hz, 1H), 4.57 (app d,2H), 6.05 (m, 1H), 6.86 (m, 1H), 6.96 (ddd, J=11.2, 8.5, 3.2 Hz, 1H),7.15 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 468.4.

EXAMPLE 60N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A solution ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (155 mg, 0.287 mmol) in MeOH (2.87 mL) was treated with DIPEA(0.100 mL, 0.575 mmol), formaldehyde (0.021 mL, 0.29 mmol), and afterstirring for 5 min, sodium triacetoxyborohydride (122 mg, 0.575 mmol).The reaction mixture was stirred for 30 min at room temperature. Thereaction mixture was filtered and purified by HPLC (Pump: Waters 2525 or2545; MS: ZQ; Software: MassLynx. A Xbridge™ C18, 5 μm, ID 30×75 mmcolumn was used and eluted with 40% to 95% of 20/80 (v/v) water/ACN (10mmol NH₄HCO₃, pH 9.5-10) and water (10 mmol NH₄HCO₃, pH 9.5-10)) to givethe title compound as an off-white semisolid (35.4 mg, 28.0%). ¹H NMR(500 MHz, methanol-d4) δ ppm 1.95 (m, 2H), 2.12 (m, 2H), 2.47 (s, 3H),2.79 (m, 4H), 2.96 (ddd, J=12.4, 8.8, 3.2 Hz, 2H), 3.35 (m, 2H), 3.49(s, 2H), 3.75 (td, J=14.6, 4.4 Hz, 2H), 4.43 (tt, J=7.7, 3.5 Hz, 1H),6.03 (m, 1H), 6.86 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.16(td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 440.4.

EXAMPLE 61 Methyl3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxylate

To a solution of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (50 mg, 0.080 mmol) and triethylamine (0.026 mL, 0.185 mmol) inDCM (0.75 mL) was added methyl carbonochloridate (9.3 μL, 0.121 mmol) at0° C. The reaction mixture was stirred at 0° C. for 1 hr, warmed to 23°C., and concentrated via rotary evaporation. The resulting crudematerial was reconstituted in DMSO, rinsed with DMSO, and purified byHPLC Method B using a 30% to 70% ACN gradient to give the title compoundas a TFA salt (11.0 mg, 23.8%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.18 (d, J=6.8 Hz, 6H), 1.82-1.94 (m, 2H), 2.02-2.12 (m,2H), 2.65 (t, J=5.9 Hz, 2H), 2.83-2.93 (m, 2H), 3.21-3.33 (m, 2H), 3.63(s, 3H), 3.64-3.68 (m, 2H), 4.06-4.17 (m, 1H), 4.34 (br s, 2H), 4.51(tt, J=8.1, 3.9 Hz, 1H), 5.51-5.65 (m, 1H), 6.99-7.05 (m, 1H), 7.25-7.35(m, 2H); ESI-MS m/z [M+H]⁺ 462.4.

EXAMPLE 623-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(2-fluoroethyl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

To a suspension of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (50 mg, 0.080 mmol) and K₂CO₃ (44.4 mg, 0.322 mmol) in acetone(2.0 mL) was added 1-bromo-2-fluoroethane (5.4 μL, 0.072 mmol) at 23° C.The reaction mixture was stirred at 23° C. for 1 h and then at 50° C.for 3 days. The reaction mixture was cooled to 23° C., an additionalportion of 1-bromo-2-fluoroethane (2.7 μL, 0.036 mmol) was added, andthe reaction mixture was heated for an additional 1.5 hr at 50° C.,cooled to 23° C., and concentrated via rotary evaporation. The resultingcrude material was reconstituted in DMSO, filtered, rinsed with DMSO,and purified by HPLC Method B using a 30% to 70% ACN gradient to givethe title compound as a TFA salt (10.7 mg, 23.6%) as a yellow film. ¹HNMR (500 MHz, DMSO-d₆, mixture of rotamers) δ ppm 1.19 (d, J=6.8 Hz,6H), 1.83-1.92 (m, 2H), 2.02-2.13 (m, 2H), 2.79-2.96 (m, 3H), 2.96-3.11(m, 0.9H), 3.24-3.36 (m, 2H), 3.38-3.55 (m, 1.1H) 3.65 (br s, 1.1H),3.71 (m, 0.9H), 3.73-3.84 (m, 1H), 4.12-4.19 (m, 1H), 4.28 (br s, 0.9H),4.30 (br s, 1.1H), 4.54 (ddd, J=11.7, 7.8, 3.9 Hz, 1H), 4.87 (t, J=4.4Hz, 0.9H), 4.88-4.95 (m, 1H), 4.97 (t, J=4.4 Hz, 1.1H), 5.86 (d, J=8.3Hz, 1H), 6.97-7.08 (m, 1H), 7.25-7.37 (m, 2H); ESI-MS m/z [M+H]⁺ 450.5.

EXAMPLE 63(R)-1-(2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

Acetic anhydride (14.1 μL, 0.149 mmol) and formic acid (38.1 μL, 0.994mmol) were combined in THF (99 μL) and stirred at room temperature for10 min. This solution was cooled to 0° C. and was added to a stirringsolution of(R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(41.7 mg, 0.099 mmol) in THF (895 μL) at 0° C. After 10 min, UPLC-MSshowed conversion not to the formylated product, but to the acetylatedproduct. The reaction mixture was treated with MeOH, concentrated underreduced pressure, taken up in MeOH, filtered, and purified by HPLCMethod B to give the title compound, as a TFA salt, as a pale yellowsolid (17.5 mg, 30.6%). ¹H NMR (500 MHz, methanol-d4, mixture ofrotamers) δ ppm 1.28 (m, 6H), 1.45 (d, J=12.7 Hz, 1H), 1.65 (m, 2H),2.01 (m, 1H), 2.09 (m, 1H), 2.18 (s, 1.1H), 2.20 (s, 1.9H), 2.76 (m,4H), 3.49 (m, 2H), 3.81 (t, J=6.1 Hz, 1.3H), 3.85 (t, J=5.9 Hz, 0.7H),4.13 (m, 1H), 4.57 (s, 0.7H), 4.61 (s, 1.3H), 5.52 (m, 1H), 7.02 (m,2H), 7.50 (m, 1H); ESI-MS m/z [M+H]⁺ 462.4.

EXAMPLE 65N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

A mixture of cyclopropanamine (13.6 mg, 0.237 mmol),3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazineTFA salt (30.9 mg, 0.059 mmol), sodium tert-butoxide (11.4 mg, 0.119mmol), BINAP (5.5 mg, 8.90 nmol) and Pd₂(dba)₃ (2.7 mg, 2.97 nmol) intoluene (200 μL) was heated at 90° C. for 14 h. The mixture was directlypurified by HPLC Method A to give the title compound as a TFA salt (12.9mg, 40.2%) as a yellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm0.53-0.58 (m, 2H), 0.75-0.81 (m, 2H), 1.86-1.96 (m, 2H), 2.02-2.12 (m,2H), 2.64-2.70 (m, 1H), 2.94-3.02 (m, 1H), 3.08-3.12 (m, 3H), 3.17-3.27(m, 3H), 3.34-3.42 (m, 2H), 3.59-3.68 (m, 2H), 3.75 (s, 3H), 4.25-4.41(m, 3H), 6.64-6.69 (m, 1H), 6.70-6.76 (m, 1H), 7.03-7.10 (m, 1H); ESI-MSm/z [M+H]⁺ 428.4.

EXAMPLE 66N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (15.8mg, 0.060 mmol),3-chloro-N-cyclopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine(12 mg, 0.050 mmol), sodium tert-butoxide (14.5 mg, 0.151 mmol), BINAP(4.7 mg, 7.54 nmol) and Pd₂(dba)₃ (2.3 mg, 2.51 nmol) in toluene (250μL) was heated at 90° C. for 14 h. The mixture was purified by HPLCMethod A to give the title compound as a TFA salt (14.4 mg, 52.9%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.56-0.62 (m, 2H),0.79-0.87 (m, 2H), 1.85-1.96 (m, 2H), 2.02-2.11 (m, 2H), 2.66-2.75 (m,1H), 2.94-3.02 (m, 2H), 3.08-3.12 (m, 3H), 3.13-3.27 (m, 2H), 3.33-3.43(m, 2H), 3.53-3.69 (m, 2H), 3.75 (s, 3H), 4.19-4.42 (m, 3H), 6.63-6.69(m, 1H) 6.73 (dd, J=12.9, 3.0 Hz, 1H), 7.02-7.09 (m, 1H); ESI-MS m/z[M+H]⁺ 428.4.

EXAMPLE 67N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of 4-((2,4-difluorophenyl)fluoromethyl)piperidinehydrochloride (16.0 mg, 0.060 mmol),3-chloro-N-cyclopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine(12 mg, 0.050 mmol), sodium tert-butoxide (14.5 mg, 0.151 mmol), BINAP(4.7 mg, 7.54 μmol) and Pd₂(dba)₃ (2.3 mg, 2.51 nmol) in toluene (250μL) was heated at 90° C. for 14 h. The mixture was purified by HPLCMethod A to give the title compound as a TFA salt (11.1 mg, 40.5%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.57 (dt, J=3.5, 1.4Hz, 2H), 0.78-0.85 (m, 2H), 1.36-1.45 (m, 1H), 1.52-1.73 (m, 2H),1.93-2.15 (m, 2H), 2.60-2.87 (m, 3H), 3.08 (s, 3H), 3.09-3.15 (m, 2H),3.38-3.74 (m, 4H), 4.26 (br s, 2H), 5.51 (dd, J=46.2, 7.3 Hz, 1H),6.96-7.08 (m, 2H), 7.45-7.53 (m, 1H); ESI-MS m/z [M+H]⁺ 432.4.

EXAMPLE 68(S)-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of (S)-4-((2,4-difluorophenyl)fluoromethyl)piperidinehydrochloride (14.7 mg, 0.055 mmol),3-chloro-N-cyclopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine(11 mg, 0.046 mmol), sodium tert-butoxide (13.3 mg, 0.138 mmol), BINAP(4.3 mg, 6.91 μmol), and Pd₂(dba)₃ (2.1 mg, 2.30 μmol) in toluene (230μL) was heated at 90° C. for 14 h. The mixture was purified by HPLCMethod A to give the title compound as a TFA salt (11.1 mg, 44.2%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.56-0.63 (m, 2H), 0.84(m, J=6.8 Hz, 2H), 1.40 (d, J=12.9 Hz, 1H), 1.52-1.74 (m, 2H), 1.92-2.14(m, 2H), 2.61-2.75 (m, 3H), 3.08 (s, 3H), 3.09-3.16 (m, 2H), 3.40-3.55(m, 2H), 3.55-3.80 (m, 2H), 4.31 (br s, 2H), 5.50 (dd, J=46.0, 7.6 Hz,1H), 6.96-7.08 (m, 2H), 7.45-7.54 (m, 1H); ESI-MS m/z [M+H]⁺ 432.4.

EXAMPLE 69(R)-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A mixture of (R)-4-((2,4-difluorophenyl)fluoromethyl)piperidinehydrochloride (14.7 mg, 0.055 mmol),3-chloro-N-cyclopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine(11 mg, 0.046 mmol), sodium tert-butoxide (13.3 mg, 0.138 mmol), BINAP(4.3 mg, 6.91 μmol) and Pd₂(dba)₃ (2.1 mg, 2.30 μmol) in toluene (230μL) was heated at 90° C. for 14 h. The mixture was purified by HPLCMethod A to give the title compound as a TFA salt (10.5 mg, 41.8%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 0.55-0.62 (m, 2H),0.79-0.87 (m, 2H), 1.40 (br d, J=12.4 Hz, 1H), 1.52-1.73 (m, 2H),1.93-2.14 (m, 2H), 2.61-2.74 (m, 3H), 3.08 (s, 3H), 3.10-3.15 (m, 2H),3.40-3.54 (m, 2H), 3.55-3.81 (m, 2H), 4.26 (br s, 2H), 5.50 (dd, J=46.2,7.8 Hz, 1H), 6.97-7.08 (m, 2H), 7.45-7.53 (m, 1H); ESI-MS m/z [M+H]⁺432.3.

EXAMPLE 703-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

Sodium triacetoxyborohydride (15.3 mg, 0.072 mmol) was added to amixture of DIPEA (9.4 mg, 0.072 mmol),3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (19.3 mg, 0.036 mmol) and formaldehyde (3 μL, 0.036 mmol) inMeOH (360 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (19.3 mg, 97%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.24 (dd, J=6.4, 2.2Hz, 6H), 1.40-1.48 (m, 1H), 1.53-1.74 (m, 2H), 1.96-2.14 (m, 2H),2.60-2.73 (m, 2H), 2.93-3.06 (br m, 2H), 3.06 (s, 3H), 3.39-3.54 (m,3H), 3.69-3.81 (m, 1H), 4.18 (dt, J=13.1, 6.4 Hz, 2H), 4.16-4.36 (br m,1H), 5.52 (dd, J=46.2, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.54 (m,1H); ESI-MS m/z [M+H]⁺ 434.4.

EXAMPLE 711-(3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

Acetic anhydride (7 μL, 0.075 mmol) was added to a solution of3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (20.1 mg, 0.038 mmol) and pyridine (9 μL, 0.113 mmol) in DCM(380 μL) at rt. After 1 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (20.1 mg, 93%) as a yellow film.¹H NMR (400 MHz, methanol-d₄) δ ppm 1.29 (dd, J=6.4, 1.9 Hz, 6H), 1.46(br s, 1H), 1.56-1.77 (m, 2H), 2.00 (d, J=12.9 Hz, 1H), 2.04-2.15 (m,1H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.76 (qd, J=12.8, 2.4 Hz, 3H), 2.87(t, J=5.9 Hz, 1H), 3.40-3.56 (m, 2H), 3.78-3.83 (m, 1.1H), 3.83-3.89 (m,0.9H), 4.09-4.17 (m, 1H), 4.52 (s, 2H), 5.53 (dd, J=46.7, 7.6 Hz, 1H),6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]⁺ 462.4.

EXAMPLE 723-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (8.4 mg, 0.078 mmol) was added to a solutionof3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (20.8 mg, 0.039 mmol) and triethylamine (16 μL, 0.117 mmol) inDCM (390 μL) at rt. After 1 h, the mixture was purified by HPLC Method Ato give the title compound as a TFA salt (20.8 mg, 88%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.31 (dd, J=6.6, 1.8 Hz, 6H),1.40-1.48 (m, 1H), 1.58-1.78 (m, 2H), 1.95-2.03 (m, 1H), 2.03-2.18 (m,1H), 2.71-2.88 (m, 4H), 2.90 (s, 6H), 3.42-3.52 (m, 2H), 3.54 (t, J=5.7Hz, 2H), 4.07-4.16 (m, 1H), 4.22-4.27 (m, 2H), 5.53 (dd, J=46.5, 7.3 Hz,1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]⁺ 491.4.

EXAMPLE 733-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (10.5 mg, 0.097 mmol) was added to a solutionof3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (25.8 mg, 0.049 mmol) and triethylamine (20.5 μL, 0.146 mmol)in DCM (500 μL) at rt. After 1 h, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (25.8 mg, 88%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.33 (d, J=6.3 Hz, 6H),1.89-2.00 (m, 2H), 2.06-2.16 (m, 2H), 2.85-2.89 (m, 2H), 2.90 (s, 6H),3.04-3.13 (m, 2H), 3.41-3.50 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.76 (s,3H), 4.08-4.18 (m, 1H), 4.27 (s, 2H), 4.35-4.42 (m, 1H), 6.67 (ddd,J=9.0, 2.9, 1.5 Hz, 1H), 6.74 (dd, J=12.9, 3.0 Hz, 1H), 7.08 (t, J=9.2Hz, 1H); ESI-MS m/z [M+H]⁺ 487.4.

EXAMPLE 742-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

Sodium triacetoxyhydroborate (9.7 mg, 0.046 mmol) was added to asolution of DIPEA (8 μL, 0.046 mmol),2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (12.1 mg, 0.023 mmol) and formaldehyde (1.9 μL, 0.023 mmol) inMeOH (229 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (12.1 mg, 97%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.24 (d, J=6.3 Hz, 6H),1.88-1.99 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.04 (m, 3H), 3.08 (br s,4H), 3.35-3.53 (m, 3H), 3.76 (br s, 4H), 4.10-4.19 (m, 1H), 4.20-4.40(m, 3H), 6.64-6.69 (m, 1H), 6.74 (dd, J=12.8, 2.1 Hz, 1H), 7.07 (t,J=9.2 Hz, 1H); ESI-MS m/z [M+H]⁺ 430.4.

EXAMPLE 752-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

Sodium triacetoxyhydroborate (11.0 mg, 0.052 mmol) was added to asolution of DIPEA (9 μL, 0.052 mmol),2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (13.9 mg, 0.026 mmol) and formaldehyde (2 μL, 0.026 mmol) inMeOH (260 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (13.9 mg, 97%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.23 (dd, J=6.4, 2.4Hz, 6H), 1.41-1.49 (m, 1H), 1.52-1.74 (m, 2H), 1.97-2.15 (m, 2H),2.61-2.75 (m, 2H), 2.89-3.04 (m, 2H), 3.07 (s, 3H), 3.40-3.56 (m, 3H),3.75 (br s, 1H), 4.13 (quin, J=6.5 Hz, 1H), 4.18-4.38 (m, 2H), 5.53 (dd,J=46.2, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.54 (m, 1H); ESI-MS m/z[M+H]⁺ 434.4.

EXAMPLE 761-(2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

Acetic anhydride (5 μL, 0.054 mmol) was added to a solution of2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (14.3 mg, 0.027 mmol) and pyridine (6.5 μL, 0.080 mmol) in DCM(270 μL) at rt. After 1 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (14.3 mg, 93%) as a yellow film.¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.23-1.31 (m,6H), 1.45 (d, J=12.9 Hz, 1H), 1.53-1.76 (m, 2H), 1.96-2.15 (m, 2H), 2.18(s, 1.2H), 2.21 (s, 1.8H), 2.67-2.84 (m, 4H), 3.38-3.55 (m, 2H),3.78-3.83 (m, 1.2H), 3.83-3.87 (m, 0.8H), 4.13 (dq, J=12.6, 6.3 Hz, 1H),4.56 (s, 0.8H), 4.59 (s, 1.2H), 5.53 (dd, J=46.2, 7.6 Hz, 1H), 6.97-7.09(m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]⁺ 462.4.

EXAMPLE 772-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (5.8 mg, 0.054 mmol) was added to a solutionof2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (14.3 mg, 0.027 mmol) and triethylamine (11 μL, 0.080 mmol) inDCM (270 μL) at rt. After 1 h, the mixture was purified by HPLC Method Ato give the title compound as a TFA salt (14.3 mg, 88%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.29 (dd, J=6.4, 1.9 Hz, 6H),1.40-1.49 (m, 1H), 1.55-1.77 (m, 2H), 2.01 (d, J=13.1 Hz, 2H), 2.70-2.84(m, 4H), 2.87-2.94 (m, 6H), 3.40-3.52 (m, 2H), 3.53-3.57 (m, 2H), 4.11(quin, J=6.4 Hz, 1H) 4.29 (s, 2H) 5.53 (dd, J=46.2, 7.3 Hz, 1H),6.97-7.09 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]⁺ 491.4.

EXAMPLE 78(5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone

Sodium triacetoxyhydroborate (6.9 mg, 0.033 mmol) was added to asolution of DIPEA (6 μL, 0.033 mmol),(5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanoneTFA salt (8.9 mg, 0.016 mmol) and formaldehyde (1.5 μL, 0.016 mmol) inMeOH (160 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (2.2 mg, 24.1%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.24 (d, J=6.6 Hz, 6H),1.81-1.94 (m, 2H), 1.96-2.05 (m, 2H), 2.85 (t, J=11.5 Hz, 2H), 3.00 (d,J=6.3 Hz, 2H), 3.07 (s, 3H), 3.44-3.53 (m, 4H), 3.71-3.82 (m, 1H),4.14-4.23 (m, 2H), 4.28-4.37 (m, 1H), 7.28 (dd, J=10.6, 8.8 Hz, 1H),7.61 (ddd, J=8.8, 4.1, 2.8 Hz, 1H), 7.75 (dd, J=6.1, 2.8 Hz, 1H); ESI-MSm/z [M+H]⁺ 446.3.

EXAMPLE 791-(3-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

Acetic anhydride (3 μL, 0.034 mmol) was added to a solution of(5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanoneTFA salt (9.2 mg, 0.017 mmol) and pyridine (4 μL, 0.051 mmol) in DCM(170 μL) at rt. After 1 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (4.0 mg, 40.4%) as a yellow film.¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.30-1.34 (m,6H), 1.88-2.04 (m, 4H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m,0.9H), 2.87-2.92 (m, 1.1H), 2.93-3.02 (m, 2H), 3.34-3.43 (m, 1H),3.50-3.59 (m, 2H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m, 0.9H), 4.08-4.17(m, 1H), 4.54 (br s, 2H), 7.25-7.32 (m, 1H), 7.59-7.63 (m, 1H), 7.76(dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 474.3.

EXAMPLE 803-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (3.8 mg, 0.036 mmol) was added to a solutionof(5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanoneTFA salt (9.7 mg, 0.018 mmol) and triethylamine (7 μL, 0.053 mmol) inDCM (180 μL) at rt. After 1 h, the mixture was purified by HPLC Method Ato give the title compound as a TFA salt (3.6 mg, 32.8%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.31-1.34 (m, 6H), 1.89-2.06(m, 4H), 2.85-2.89 (m, 2H), 2.90-2.92 (m, 6H), 2.93-3.02 (m, 2H),3.35-3.41 (m, 1H), 3.50-3.58 (m, 4H), 4.08-4.16 (m, 1H), 4.27 (s, 2H),7.29 (dd, J=10.6, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.0, 2.8 Hz, 1H), 7.76(dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 504.4.

EXAMPLE 813-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

Sodium triacetoxyhydroborate (12.3 mg, 0.058 mmol) was added to asolution of DIPEA (10 μL, 0.058 mmol),3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15.0 mg, 0.029 mmol) and formaldehyde (2 μL, 0.029 mmol) inMeOH (290 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (12.3 mg, 80%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.25 (d, J=6.6 Hz, 6H),1.90-2.00 (m, 2H), 2.07-2.16 (m, 2H), 2.96-3.05 (m, 3H), 3.08 (br s,4H), 3.33-3.42 (m, 2H), 3.43-3.85 (m, 2H), 4.14-4.38 (m, 3H), 4.44-4.51(m, 1H), 6.84-6.91 (m, 1H), 6.95-7.02 (m, 1H), 7.17 (td, J=9.2, 5.6 Hz,1H); ESI-MS m/z [M+H]⁺ 418.3.

EXAMPLE 821-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

Acetic anhydride (5 μL, 0.058 mmol) was added to a solution of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15.1 mg, 0.029 mmol) and pyridine (7 μL, 0.088 mmol) in DCM(290 μL) at rt. After 1 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (12.7 mg, 78%) as a yellow film.¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.33 (d, J=6.6Hz, 6H), 1.91-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.19 (s, 1.4H), 2.21 (s,1.6H), 2.77-2.83 (m, 0.9H), 2.88-2.94 (m, 1.1H), 3.12 (td, J=8.5, 4.0Hz, 2H), 3.43-3.51 (m, 2H), 3.80-3.85 (m, 1.1H), 3.86-3.91 (m, 0.9H),4.10-4.18 (m, 1H), 4.47-4.54 (m, 1H), 4.55 (br s, 2H), 6.85-6.92 (m,1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 446.4.

EXAMPLE 833-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (6.4 mg, 0.059 mmol) was added to a solutionof3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15.3 mg, 0.030 mmol) and triethylamine (12 μL, 0.089 mmol) inDCM (300 μL) at rt. After 1 h, the mixture was purified by HPLC Method Ato give the title compound as a TFA salt (11.1 mg, 63.8%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.31 (d, J=6.3 Hz, 6H),1.91-2.01 (m, 2H), 2.09-2.18 (m, 2H), 2.86 (t, J=5.7 Hz, 2H), 2.90 (s,6H), 3.03-3.11 (m, 2H), 3.39-3.47 (m, 2H), 3.55 (t, J=5.7 Hz, 2H), 4.14(quin, J=6.4 Hz, 1H), 4.27 (s, 2H), 4.49 (tt, J=7.3, 3.6 Hz, 1H),6.84-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2,5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 475.4.

EXAMPLE 842-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

Sodium triacetoxyhydroborate (9.9 mg, 0.047 mmol) was added to asolution of DIPEA (8 μL, 0.047 mmol),2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (12.1 mg, 0.023 mmol) and formaldehyde (2 μL, 0.023 mmol) inMeOH (230 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (8.9 mg, 71.6%) as ayellow film. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.24 (d, J=6.3 Hz, 6H),1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.95-3.06 (m, 3H), 3.12 (br s,4H), 3.35-3.53 (m, 3H), 3.76 (br s, 1H), 4.15 (dt, J=13.1, 6.5, 6.5 Hz,1H), 4.19-4.38 (m, 2H), 4.48 (tt, J=7.3, 3.7 Hz, 1H), 6.85-6.92 (m, 1H),6.99 (ddd, J=11.4, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 418.3.

EXAMPLE 852-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (5.2 mg, 0.049 mmol) was added to a solutionof2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (12.6 mg, 0.024 mmol) and triethylamine (10 μL, 0.073 mmol) inDCM (240 μL) at rt. After 1 h, the mixture was purified by HPLC Method Ato give the title compound as a TFA salt (8.0 mg, 55.8%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.28 (d, J=6.6 Hz, 6H),1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.77-2.84 (m, 2H), 2.91 (s, 6H),2.99-3.08 (m, 2H), 3.35-3.44 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 4.09-4.17(m, 1H), 4.29 (s, 2H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (s,1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 475.4.

EXAMPLE 86(5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone

Sodium triacetoxyhydroborate (6.5 mg, 0.031 mmol) was added to asolution of DIPEA (5 μL, 0.031 mmol),(5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanoneTFA salt (8.4 mg, 0.015 mmol) and formaldehyde (1.5 μL, 0.015 mmol) inMeOH (150 μL) at rt. After 30 min, the mixture was purified by HPLCMethod A to give the title compound as a TFA salt (4.7 mg, 54.6%) as ayellow solid. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.24 (d, J=6.6 Hz,6H), 1.82-1.93 (m, 2H), 1.97-2.05 (m, 2H), 2.81-3.05 (m, 4H), 3.08 (s,3H), 3.35-3.54 (m, 4H), 3.72-3.83 (m, 1H), 4.10-4.18 (m, 1H), 4.19-4.40(m, 2H), 7.25-7.32 (m, 1H), 7.61 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.75(dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 446.3.

EXAMPLE 871-(2-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

Acetic anhydride (3 μL, 0.029 mmol) was added to a solution of(5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanoneTFA salt (8.0 mg, 0.015 mmol) and pyridine (4 μL, 0.044 mmol) in DCM(150 μL) at rt. After 1 h, the mixture was purified by HPLC Method A togive the title compound as a TFA salt (3.6 mg, 42%) as a yellow solid.¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.26-1.32 (m,6H), 1.84-1.96 (m, 2H), 1.97-2.06 (m, 2H), 2.19 (s, 1.1H), 2.21 (s,1.9H), 2.70-2.76 (m, 0.7H), 2.80-2.86 (m, 1.3H), 2.87-3.00 (m, 2H),3.34-3.41 (m, 1H), 3.46-3.56 (m, 2H), 3.79-3.84 (m, 1.3H), 3.84-3.89 (m,0.7H), 4.07-4.18 (m, 1H), 4.57 (s, 1.1H), 4.62 (s, 0.9H), 7.28 (dd,J=10.4, 8.8 Hz, 1H), 7.61 (ddd, J=8.9, 4.2, 2.9 Hz, 1H), 7.76 (dd,J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 474.3.

EXAMPLE 882-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-3-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

Dimethylcarbamic chloride (3.2 mg, 0.029 mmol) was added to a solutionof(5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanoneTFA salt (8.0 mg, 0.015 mmol) and triethylamine (6 μL, 0.044 mmol) inDCM (150 μL) at rt. After 1 h, the mixture was purified by HPLC Method Ato give the title compound as a TFA salt (3.9 mg, 43.1%) as a yellowsolid. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.31 (d, J=6.6 Hz, 6H),1.85-2.05 (m, 4H), 2.77-2.84 (m, 2H), 2.91 (s, 6H), 2.93-3.01 (m, 2H),3.36-3.41 (m, 1H), 3.51-3.59 (m, 4H), 4.07-4.15 (m, 1H), 4.31 (s, 2H),7.28 (dd, J=10.4, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.76(dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 504.4.

EXAMPLE 891-(2-(tert-butylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

A solution ofN-(tert-butyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (16 mg, 0.030 mmol), acetic anhydride (5.7 μL, 0.060 mmol), andDIPEA (15.8 μL, 0.090 mmol) in DCM (151 μL) was stirred at roomtemperature overnight. The crude reaction mixture was diluted in DMF,filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (15 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄,mixture of rotamers) δ ppm 1.48 (s, 9H), 1.87-1.98 (m, 2H), 2.07-2.17(m, 2H), 2.19 (s, 1.3H), 2.21 (s, 1.7H), 2.74 (t, J=5.9 Hz, 0.9H), 2.84(t, J=5.9 Hz, 1.1H), 2.97 (ddd, J=12.4, 8.6, 3.3 Hz, 2H), 3.33-3.37 (m,2H), 3.80 (t, J=5.9 Hz, 1.1H), 3.85 (t, J=5.9 Hz, 0.9H), 4.43-4.51 (m,1H), 4.53 (d, J=1.3 Hz, 2H), 6.88 (ddddd, J=9.1, 8.1, 2.9, 1.9, 0.8 Hz,1H), 6.95-7.02 (m, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺460.4.

EXAMPLE 902-(tert-butylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A solution ofN-(tert-butyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (16 mg, 0.030 mmol), dimethylcarbamic chloride (3.2 mg, 0.030mmol), and DIPEA (5.3 μL, 0.030 mmol) in DCM (151 μL) was stirred atroom temperature overnight. The crude reaction mixture was diluted inDMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (10 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄) δppm 1.48 (s, 9H), 1.87-1.97 (m, 2H), 2.07-2.17 (m, 2H), 2.82 (t, J=5.9Hz, 2H), 2.90 (s, 6H), 2.95 (ddd, J=12.2, 8.5, 3.3 Hz, 2H), 3.29-3.35(m, 2H), 3.53 (t, J=5.8 Hz, 2H), 4.25 (s, 2H), 4.46 (tt, J=7.5, 3.8 Hz,1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td,J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 489.4.

EXAMPLE 911-(2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15 mg, 0.028 mmol), acetic anhydride (5.2 μL, 0.056 mmol), andDIPEA (14.6 μL, 0.083 mmol) in DCM (139 μL) was stirred at roomtemperature overnight. The crude reaction mixture was diluted in DMF,filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (13 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄,mixture of rotamers) δ ppm 1.91-2.03 (m, 2H), 2.09-2.17 (m, 2H), 2.19(s, 1.3H), 2.21 (s, 1.7H), 2.75 (t, J=5.9 Hz, 0.9H), 2.85 (t, J=5.9 Hz,1.1H), 2.95-3.05 (m, 2H), 3.34-3.42 (m, 2H), 3.73-3.79 (m, 2H), 3.81 (t,J=5.9 Hz, 1.2H), 3.86 (t, J=6.1 Hz, 0.8H), 4.46 (tq, J=7.9, 3.9 Hz, 1H),4.56 (d, J=0.8 Hz, 2H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98(dddd, J=11.4, 8.5, 3.0, 1.0 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H);ESI-MS m/z [M+H]⁺ 468.3.

EXAMPLE 921-(2-(cyclobutylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

A mixture ofN-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10 mg, 0.018 mmol), acetic anhydride (3.8 mg, 0.037 mmol) andpyridine (4.4 mg, 0.055 mmol) in DCM (190 μL) was stirred at roomtemperature for 30 min. The mixture was purified by HPLC Method A togive the title compound as a TFA salt (6.4 mg, 59%) as a yellow film. ¹HNMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.76-1.86 (m, 2H),1.89-2.00 (m, 2H), 2.01-2.15 (m, 4H), 2.19 (s, 1.4H), 2.20 (s, 1.6H),2.38-2.48 (m, 2H), 2.73-2.79 (m, 0.9H), 2.81-2.88 (m, 1.1H), 2.99-3.08(m, 2H), 3.38-3.47 (m, 2H), 3.76 (s, 3H), 3.78-3.83 (m, 1.1H), 3.83-3.88(m, 0.9H), 4.32-4.48 (m, 2H), 4.54 (s, 2H), 6.64-6.70 (m, 1H), 6.74 (dd,J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]⁺ 470.4.

EXAMPLE 932-(cyclobutylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A mixture ofN-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10.6 mg, 0.020 mmol), dimethylcarbamic chloride (4.2 mg, 0.039mmol) and triethylamine (5.9 mg, 0.059 mmol) in DCM (200 μL) was stirredat room temperature for 30 min. The mixture was purified by HPLC MethodA to give the title compound as a TFA salt (7.1 mg, 59.2%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.77-1.87 (m, 2H), 1.90-2.00(m, 2H), 2.03-2.15 (m, 4H), 2.39-2.49 (m, 2H), 2.81-2.87 (m, 2H), 2.90(s, 6H), 2.98-3.08 (m, 2H), 3.38-3.47 (m, 2H), 3.54 (t, J=5.8 Hz, 2H),3.76 (s, 3H), 4.26 (s, 2H), 4.33-4.47 (m, 2H), 6.67 (dd, J=9.1, 1.5 Hz,1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z[M+H]⁺ 499.4.

EXAMPLE 941-(3-(cyclobutylamino)-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

A mixture ofN-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (10.1 mg, 0.019 mmol), acetic anhydride (3.8 mg, 0.037 mmol)and pyridine (4 mg, 0.056 mmol) in DCM (190 μL) was stirred at roomtemperature for 30 min. The mixture was purified by HPLC Method A togive the title compound as a TFA salt (9.7 mg, 89%) as a yellow film. ¹HNMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.78-1.87 (m, 2H),1.91-2.01 (m, 2H), 2.03-2.16 (m, 4H), 2.19 (s, 1.2H), 2.21 (s, 1.8H),2.38-2.50 (m, 2H), 2.70-2.76 (m, 0.8H), 2.80-2.87 (m, 1.2H), 3.00-3.11(m, 2H), 3.40-3.50 (m, 2H), 3.76 (s, 3H), 3.79-3.83 (m, 1.2H), 3.84-3.88(m, 0.8H), 4.34-4.48 (m, 2H), 4.57 (s, 0.8H), 4.61 (s, 1.2H), 6.64-6.69(m, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MSm/z [M+H]⁺ 470.4.

EXAMPLE 953-(cyclobutylamino)-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A mixture ofN-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (9.1 mg, 0.017 mmol), dimethylcarbamic chloride (3.6 mg, 0.034mmol) and triethylamine (5.1 mg, 0.050 mmol) in DCM (170 μL) was stirredat room temperature for 30 min. The mixture was purified by HPLC MethodA to give the title compound as a TFA salt (6.0 mg, 58.3%) as a yellowfilm. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.74-1.84 (m, 2H), 1.89-2.04(m, 4H), 2.06-2.15 (m, 2H), 2.36-2.46 (m, 2H), 2.79 (t, J=5.7 Hz, 2H),2.90 (s, 6H), 2.94-3.02 (m, 2H), 3.34-3.43 (m, 2H), 3.51-3.56 (m, 2H),3.76 (s, 3H), 4.26 (s, 2H), 4.43 (s, 2H), 6.64-6.69 (m, 1H), 6.74 (dd,J=12.9, 3.0 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]⁺ 499.4.

EXAMPLE 963-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A solution ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.028 mmol), dimethylcarbamic chloride (3.0 mg, 0.028mmol), and DIPEA (4.9 μL, 0.028 mmol) in DCM (278 μL) was stirred atroom temperature overnight. The crude reaction mixture was diluted inDMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method to give the title compound asa TFA salt (5 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄) δ ppm1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.82 (t, J=5.8 Hz, 2H), 2.90 (s,6H), 2.99 (ddd, J=12.4, 8.6, 3.4 Hz, 2H), 3.34-3.41 (m, 2H), 3.55 (t,J=5.8 Hz, 2H), 3.77 (td, J=14.5, 4.3 Hz, 2H), 4.28 (s, 2H), 4.42-4.49(m, 1H), 5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.6,3.0 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 497.4.

EXAMPLE 97N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (17 mg, 0.032 mmol), DIPEA (12.2 mg, 0.095 mmol) andmethanesulfonyl chloride (4.9 μL, 0.063 mmol) in DCM (315 μL) wasstirred at room temperature overnight. The crude reaction mixture wasdiluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR), and purified via HPLC Method A to give thetitle compound as a TFA salt (6 mg) as a clear oil. ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.88 (t, J=5.9Hz, 2H), 2.93 (s, 3H), 3.00 (ddd, J=12.4, 8.8, 3.3 Hz, 2H), 3.34-3.42(m, 2H), 3.57 (t, J=5.9 Hz, 2H), 3.78 (td, J=14.5, 4.3 Hz, 2H), 4.28 (s,2H), 4.46 (tt, J=7.5, 3.6 Hz, 1H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H),6.98 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 504.3.

EXAMPLE 981-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (17 mg, 0.032 mmol), DIPEA (12.2 mg, 0.095 mmol), and2,2-difluoroacetic anhydride (8.2 mg, 0.047 mmol) in DCM (315 μL) wasstirred at room temperature overnight. The crude reaction mixture wasdiluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR), and purified via HPLC Method A to give thetitle compound as a TFA salt (5 mg) as a clear oil. ¹H NMR (400 MHz,methanol-d₄, mixture of rotamers) δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m,2H), 2.81 (t, J=5.9 Hz, 0.8H), 2.87 (t, J=5.9 Hz, 1.2H), 2.97-3.05 (m,2H), 3.35-3.43 (m, 2H), 3.78 (td, J=14.5, 4.3 Hz, 2H), 3.87-3.96 (m,2H), 4.42-4.50 (m, 1H), 4.60 (s, 1.2H), 4.62 (s, 0.8H), 5.89-6.22 (m,1H), 6.41-6.71 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.6, 3.0Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 504.3.

EXAMPLE 99(S)-1-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-1-one

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (17 mg, 0.032 mmol), HATU (13.2 mg, 0.035 mmol), and DIPEA(12.2 mg, 0.095 mmol) in DMF (158 μL) was stirred for 10 min. Then,(S)-2-methoxypropanoic acid (3.6 mg, 0.035 mmol) was added at roomtemperature and the resulting reaction mixture stirred overnight. Thecrude reaction mixture was diluted in DMF, filtered through ahydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purifiedvia HPLC Method A to give the title compound as a TFA salt (6 mg) as aclear oil. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.32(d, J=6.6 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.7H), 1.91-2.02 (m, 2H),2.09-2.18 (m, 2H), 2.77 (t, J=5.8 Hz, 0.9H), 2.85 (t, J=4.9 Hz, 1.1H),2.96-3.05 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.78 (td, J=14.5,4.3 Hz, 2H), 3.84-3.97 (m, 2H), 4.31-4.40 (m, 1H), 4.42-4.49 (m, 1H),4.59 (m, 0.9H), 4.67 (m, 1.1H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H),6.98 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H);ESI-MS m/z [M+H]⁺ 512.4.

EXAMPLE 1001-(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

A solution ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.028 mmol), DIPEA (10.8 mg, 0.083 mmol) andmethanesulfonyl chloride (4.3 μL, 0.056 mmol) in DCM (280 μL) wasstirred at room temperature for 2 h. The crude reaction mixture wasdiluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR), and purified via HPLC Method A to give thetitle compound as a TFA salt (3 mg) as a clear oil. ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.87 (t, J=5.9Hz, 2H), 2.93 (s, 3H), 2.96-3.04 (m, 2H), 3.34-3.42 (m, 2H), 3.57 (t,J=5.8 Hz, 2H), 3.76 (td, J=14.5, 4.3 Hz, 2H), 4.28 (s, 2H), 4.42-4.49(m, 1H), 5.89-6.21 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5,3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 504.4.

EXAMPLE 1011-(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

A solution ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.028 mmol), DIPEA (10.8 mg, 0.083 mmol), and2,2-difluoroacetic anhydride (7.3 mg, 0.042 mmol) in DCM (278 μL) wasstirred at room temperature for 2 h. The crude reaction mixture wasdiluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR), and purified via HPLC Method A to give thetitle compound as a TFA salt (3 mg) as a clear oil. ¹H NMR (400 MHz,methanol-d₄, mixture of rotamers) δ ppm 1.92-2.02 (m, 2H), 2.09-2.17 (m,2H), 2.80 (t, J=5.9 Hz, 0.8H), 2.86 (t, J=5.4 Hz, 1.2H), 2.96-3.04 (m,2H), 3.34-3.43 (m, 2H), 3.77 (td, J=14.3, 4.0 Hz, 2H), 3.90 (t, J=5.8Hz, 1.2H), 3.93 (t, J=6.1 Hz, 0.8H), 4.46 (tt, J=7.6, 3.7 Hz, 1H), 4.61(s, 0.8H), 4.63 (s, 1.2H), 5.89-6.21 (m, 1H), 6.42-6.71 (m, 1H),6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2,5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 504.4.

EXAMPLE 102(S)-1-(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-1-one

A solution of (S)-2-methoxypropanoic acid (2.9 mg, 0.028 mmol), DIPEA(3.9 mg, 0.028 mmol), and HATU (10.6 mg, 0.028 mmol) in DMF (278 μL) wasstirred at room temperature for 10 min then treated withN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.028 mmol). Stirring was continued overnight. Thecrude reaction mixture was diluted in DMF, filtered through ahydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purifiedvia HPLC Method A to give the title compound as a TFA salt (3 mg) as aclear oil. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.32(d, J=6.6 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.7H), 1.91-2.04 (m, 2H),2.09-2.19 (m, 2H), 2.76 (t, J=6.2 Hz, 0.9H), 2.84 (t, J =5.4 Hz, 1.1H),2.95-3.05 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.78 (td, J=14.6,4.3 Hz, 2H), 3.83-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.49 (m, 1H),4.56 (m, 1.1H), 4.68 (m, 0.9H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H),6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H);ESI-MS m/z [M+H]⁺ 512.4.

EXAMPLE 103(R)-1-(3-(2,2-difluoroethylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-1-one

A solution of (R)-2-methoxypropanoic acid (2.9 mg, 0.028 mmol), DIPEA(10.8 mg, 0.083 mmol), and HATU (10.6 mg, 0.028 mmol) in DMF (278 μL)was stirred at room temperature for 10 min followed by the addition ofN-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (15 mg, 0.028 mmol) and stirring overnight. The crude reactionmixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μmfilter (Millipore® Millex-LCR), and purified via HPLC Method A to givethe title compound as a TFA salt (3 mg) as a clear oil. ¹H NMR (400 MHz,methanol-d₄, mixture of rotamers) δ ppm 1.32 (d, J=6.8 Hz, 1.3H), 1.38(d, J=6.6 Hz, 1.6H), 1.90-2.04 (m, 2H), 2.09-2.18 (m, 2H), 2.76 (t,J=6.6 Hz, 0.9H), 2.84 (t, J=6.1 Hz, 1.1H), 3.00 (ddd, J=12.3, 8.6, 3.3Hz, 2H), 3.33 (s, 3H), 3.34-3.43 (m, 2H), 3.72-3.84 (m, 2H), 3.84-3.98(m, 2H), 4.32-4.41 (m, 1H), 4.42-4.50 (m, 1H), 4.51-4.55 (m, 0.6H),4.62-4.69 (m, 1.4H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd,J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z[M+H]⁺ 512.4.

EXAMPLE 1041-(2-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to Example 29 usingN-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm0.78-0.84 (m, 2H), 1.01-1.07 (m, 2H), 1.47 (d, J=6.8 Hz, 2H), 1.60 (d,J=6.8 Hz, 1H), 1.90-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.23 (s, 3H), 2.76(tt, J=6.9, 3.5 Hz, 1H), 2.85-2.96 (m, 2H), 2.99-3.20 (m, 3H), 3.46-3.60(m, 3H), 4.14 (dd, J=13.6, 5.6 Hz, 0.5H), 4.52 (td, J=7.4, 3.4 Hz, 1H),5.38 (q, J=6.6 Hz, 0.5H), 6.86-6.94 (m, 1H), 7.01 (ddd, J=11.2, 8.5, 3.0Hz, 1H), 7.19 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 458.35.

EXAMPLE 1052-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N,5-trimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

The title compound was prepared in a manner similar to Example 55 usingN-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt. ¹H NMR (400 MHz, methanol-d4) δ ppm 0.82-0.89 (m, 1H),1.05-1.12 (m, 1H), 1.53-1.58 (m, 3H), 1.92-2.04 (m, 2H), 2.10-2.20 (m,2H), 2.63-2.87 (m, 2H), 2.91-2.94 (m, 5H), 3.02-3.25 (m, 3H), 3.35-3.59(m, 3H), 3.78-3.86 (m, 1H), 4.49-4.57 (m, 1H), 4.66 (q, J=6.8 Hz, 1H),6.86-6.94 (m, 1H), 6.97-7.05 (m, 1H), 7.15-7.25 (m, 1H); ESI-MS m/z[M+H]⁺ 487.40.

EXAMPLE 106N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6-dimethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution ofN-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15 mg, 0.028 mmol), formaldehyde (1.5 μL, 0.057 mmol), andDIPEA (5.0 μL, 0.028 mmol) in DCM (283 μL) was stirred for 10 min. Tothis was then added sodium triacetoxyborohydride (18.0 mg, 0.085 mmol)and the reaction mixture was stirred overnight. Purification by HPLCMethod A afforded the title compound as a TFA salt (4 mg). ¹H NMR (400MHz, methanol-d4) δ ppm 0.60-0.67 (m, 2H), 0.83-0.92 (m, 2H), 1.64-1.80(m, 3H), 1.87-2.04 (m, 2H), 2.05-2.21 (m, 2H), 2.74 (tt, J=7.0, 3.6 Hz,1H), 2.98-3.21 (m, 7H), 3.35-3.51 (m, 2H), 3.59 (d, J=6.6 Hz, 1H), 3.78(br s, 1H), 4.42 (br s, 1H), 4.49 (td, J=7.4, 3.7 Hz, 1H), 6.86-6.93 (m,1H), 6.96-7.05 (m, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H).

EXAMPLE 1071-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15 mg, 0.027 mmol), acetic anhydride (5.1 μL, 0.054 mmol), andDIPEA (14.2 μL, 0.081 mmol) in DCM (136 μL) was stirred at roomtemperature overnight. The crude reaction mixture was diluted in DMF,filtered through a hydrophilic PTFE 0.45 nm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (8 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄,mixture of rotamers) δ ppm 1.13 (d, J=6.8 Hz, 1.4H), 1.23 (d, J=6.8 Hz,1.6H), 1.92-2.03 (m, 2H), 2.09-2.17 (m, 2H), 2.18 (s, 1.4H), 2.22 (s,1.6H), 2.54-2.67 (m, 1H), 2.95-3.04 (m, 2.4H), 3.13 (dd, J=16.7, 6.3 Hz,0.6H), 3.34-3.44 (m, 2H), 3.74-3.83 (m, 2.4H), 3.99 (d, J=18.2 Hz,0.6H), 4.40-4.49 (m, 1H), 4.55 (quin, J=6.6 Hz, 0.5H), 4.66 (d, J=16.7Hz, 0.5H), 5.07 (d, J=17.7 Hz, 0.5H), 5.18 (m, 0.5H), 5.90-6.22 (m, 1H),6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2,5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 481.9.

EXAMPLE 1082-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N,7-trimethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxamide

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15 mg, 0.027 mmol), dimethylcarbamic chloride (5.8 mg, 0.054mmol), and DIPEA (14.2 μL, 0.081 mmol) in DCM (136 μL) was stirred atroom temperature overnight. The crude reaction mixture was diluted inDMF, filtered through a hydrophilic PTFE 0.45 nm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (10 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄) δppm 1.19 (d, J=6.8 Hz, 3H), 1.92-2.02 (m, 2H), 2.09-2.19 (m, 2H), 2.53(d, J=17.2 Hz, 1H), 2.88 (s, 6H), 3.00 (ddd, J=12.3, 8.6, 3.3 Hz, 2H),3.15 (dd, J=16.8, 5.9 Hz, 1H), 3.34-3.42 (m, 2H), 3.73-3.84 (m, 2H),4.2-4.34 (m, 3H), 4.46 (tt, J=7.6, 3.6 Hz, 1H), 5.89-6.22 (m, 1H),6.85-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2,5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 511.1.

EXAMPLE 109N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (15 mg, 0.027 mmol), formaldehyde (4.0 μL, 0.054 mmol), andDIPEA (4.7 μL, 0.027 mmol) in DCM (136 μL) was stirred for 10 min atroom temperature then treated with sodium triacetoxyborohydride (17.2mg, 0.081 mmol). The resulting reaction mixture was stirred overnight.The crude reaction mixture was diluted in DMF, filtered through ahydrophilic PTFE 0.45 nm filter (Millipore® Millex-LCR), and purifiedvia HPLC Method A to give the title compound as a TFA salt (8 mg) as aclear oil. ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.39-1.57 (m, 3H),1.92-2.03 (m, 2H), 2.08-2.18 (m, 2H), 2.82-3.09 (m, 6H), 3.16 (d, J=14.9Hz, 1H), 3.35-3.44 (m, 2H), 3.67-3.85 (m, 3H), 4.11-4.29 (m, 1H),4.37-4.44 (m, 1H), 4.44-4.52 (m, 1H), 5.90-6.22 (m, 1H), 6.85-6.91 (m,1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H);ESI-MS m/z [M+H]⁺ 453.9.

EXAMPLE 1101-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-7,8-dihydropyrido[4,3-b]pyrazin-6(5H)-yl)-2,2-difluoroethanone

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10 mg, 0.018 mmol), 2,2-difluoroacetic anhydride (4.7 mg,0.027 mmol), and DIPEA (7.0 mg, 0.054 mmol) in DCM (90 μL) was stirredat room temperature for 2 h. The crude reaction mixture was diluted inDMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (5 mg) as a white solid. ¹H NMR (400 MHz, methanol-d₄,mixture of rotamers) δ ppm 1.21 (d, J=7.1 Hz, 1.2H), 1.29 (d, J=6.6 Hz,1.8H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.58-2.69 (m, 1H),2.98-3.07 (m, 2.4H), 3.11-3.17 (m, 0.6H), 3.35-3.44 (m, 2H), 3.78 (td,J=14.5, 4.3 Hz, 2H), 4.11 (d, J=17.2 Hz, 1H), 4.42-4.51 (m, 1H),4.60-4.67 (m, 0.6H), 4.73-4.77 (m, 0.4H), 5.05 (d, J=17.7 Hz, 0.6H),5.11-5.18 (m, 0.4H), 5.89-6.22 (m, 1H), 6.39-6.73 (m, 1H), 6.85-6.91 (m,1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H);ESI-MS m/z [M+H]⁺ 517.9.

EXAMPLE 1111-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethanone

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10 mg, 0.018 mmol), 2-methoxyacetyl chloride (2.9 mg, 0.027mmol), and DIPEA (7.0 mg, 0.054 mmol) in DCM (90 μL) was stirred at roomtemperature for 2 h. The crude reaction mixture was diluted in DMF,filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (4 mg) as a white solid. ¹H NMR (400 MHz, methanol-d₄,mixture of rotamers) δ ppm 1.16 (d, J=6.8 Hz, 1.4H), 1.24 (d, J=6.6 Hz,1.6H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.59 (dd, J=16.9, 10.6 Hz,1H), 2.97-3.00 (m, 2.4H), 3.09-3.15 (m, 0.6H), 3.35-3.41 (m, 2H), 3.43(s, 3H), 3.78 (td, J=14.6, 4.3 Hz, 2H), 4.03 (d, J=17.9 Hz, 0.6H),4.19-4.27 (m, 1.4H), 4.29-4.39 (m, 1H), 4.46-4.52 (m, 1.5H), 4.58-4.62(m, 0.5H), 5.07 (d, J=18.8 Hz, 0.5H), 5.18 (t, J=5.3 Hz, 0.5H),5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz,1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 511.9.

EXAMPLE 112N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

A solution ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10 mg, 0.018 mmol), methanesulfonyl chloride (3.1 mg, 0.027mmol), and DIPEA (7.0 mg, 0.054 mmol) in DCM (181 μL) was stirred atroom temperature for 2 h. The crude reaction mixture was diluted in DMF,filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give the title compoundas a TFA salt (4 mg) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δppm 1.25 (d, J=6.8 Hz, 3H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.57(d, J=16.9 Hz, 1H), 2.94 (s, 3H), 3.01 (t, J=10.9 Hz, 2H), 3.14 (dd,J=16.7, 6.3 Hz, 1H), 3.34-3.43 (m, 2H), 3.78 (td, J=14.5, 4.3 Hz, 2H),4.17-4.25 (m, 1H), 4.43-4.55 (m, 3H), 5.89-6.22 (m, 1H), 6.84-6.91 (m,1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H);ESI-MS m/z [M+H]⁺ 517.9.

EXAMPLE 113(2S)-1-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-1-one

A solution of (S)-2-methoxypropanoic acid (1.9 mg, 0.018 mmol), DIPEA(7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (90 μL) wasstirred at room temperature for 10 min then treated withN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirredfor 2 h. The crude reaction mixture was diluted in DMF, filtered througha hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purifiedvia HPLC Method A to give the title compound as a TFA salt (5 mg) as awhite solid. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm1.17 (t, J=6.7 Hz, 1.4H), 1.27 (dd, J=6.7, 2.7 Hz, 1.6H), 1.33 (dd,J=11.5, 6.7 Hz, 1.4H), 1.38 (dd, J=6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m,2H), 2.09-2.19 (m, 2H), 2.58 (m, 0.6H), 2.64 (m, 0.4H), 2.95-3.05 (m,2H), 3.08-3.10 (m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.44(m, 2H), 3.71-3.86 (m, 2H), 4.03 (t, J=18.3 Hz, 1H), 4.30-4.41 (m, 1H),4.43-4.50 (m, 1H), 4.70-4.83 (m, 1H), 5.08 (m, 0.5H), 5.21 (m, 0.5H),5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz,1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 525.9.

EXAMPLE 114(2R)-1-(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-1-one

A solution of (R)-2-methoxypropanoic acid (1.9 mg, 0.018 mmol), DIPEA(7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (90 μL) wasstirred for 10 min at room temperature then treated withN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirredfor 2 h. The crude reaction mixture was diluted in DMF, filtered througha hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purifiedvia HPLC Method A to give the title compound as a TFA salt (5 mg) as awhite solid. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm1.17 (t, J=6.6 Hz, 1.4H), 1.27 (dd, J=6.7, 2.7 Hz, 1.6H), 1.33 (dd,J=11.6, 6.8 Hz, 1.4H), 1.38 (dd, J =6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m,2H), 2.09-2.18 (m, 2H), 2.53-2.68 (m, 1H), 2.94-3.05 (m, 2H), 3.08-3.10(m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.42 (m, 2H), 3.78(td, J=14.5, 4.2 Hz, 2H), 4.03 (t, J=18.8 Hz, 1H), 4.30-4.41 (m, 1H),4.43-4.51 (m, 1H), 4.70-4.82 (m, 1H), 5.03-5.14 (m, 0.5H), 5.18-5.23 (m,0.5H), 5.90-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J=11.3, 8.5, 2.9Hz, 1H), 7.18 (td, J=9.2, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 525.9.

EXAMPLE 115Cyclopropyl(2-(2,2-difluoroethylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone

A solution of cyclopropanecarboxylic acid (1.6 mg, 0.018 mmol), DIPEA(7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (181 μL) wasstirred at room temperature for 10 min followed by the addition ofN-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirredfor 2 h. The crude reaction mixture was diluted in DMF, filtered througha hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purifiedvia HPLC Method A to give the title compound as a TFA salt (5 mg) as awhite solid. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm0.80-1.01 (m, 4H), 1.13 (d, J=6.6 Hz, 1.4H), 1.27 (d, J=6.3 Hz, 1.6H),1.91-2.04 (m, 2H), 2.06-2.20 (m, 2H), 2.56-2.60 (m, 0.5H), 2.66-2.70 (m,0.5H), 3.02 (br s, 2H), 3.13-3.15 (m, 0.5H), 3.16-3.20 (m, 0.5H),3.34-3.46 (m, 2H), 3.72-3.87 (m, 2H), 4.04 (d, J=18.2 Hz, 1H), 4.41-4.58(m, 2H), 5.02 (d, J=17.4 Hz, 1.4H), 5.15-5.19 (m, 0.6H), 5.90-6.23 (m,1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td,J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 507.9.

EXAMPLE 1166-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine

To a suspension of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (50 mg, 0.080 mmol) and Cs₂CO₃ (92 mg, 0.281 mmol) in DMF (0.5mL) was added 1,1-difluoro-2-iodoethane (0.071 mL, 0.804 mmol) at 23° C.The reaction mixture was stirred at 80° C. for 18 h. The resulting crudematerial was filtered, rinsed with DMSO (2×0.5 mL), and purified by HPLCMethod B using a 30% to 70% ACN gradient to give the title compound as aTFA salt (6.1 mg, 13%) as a yellow film. ¹FINMR (500 MHz, DMSO-d₆) δ ppm1.19 (d, J=6.4 Hz, 6H), 1.82-1.93 (m, 2H), 2.03-2.10 (m, 2H), 2.79-2.98(m, 4H), 3.24-3.32 (m, 2H), 3.33-3.75 (m, 4H), 4.05-4.18 (m, 3H),4.52-4.55 (m, 1H), 5.76-5.82 (m, 1H), 6.39-6.72 (m, 1H), 7.00-7.04 (m,1H), 7.25-7.34 (m, 2H); ESI-MS m/z [M+H]⁺ 468.3.

EXAMPLE 117(S)-1-(2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

A solution of(S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (56.0 mg, 0.105 mmol) in DCM (1.05 mL) at 0° C. was treatedwith acetic anhydride (19.8 μL, 0.210 mmol) and pyridine (25.5 μL, 0.315mmol). The reaction mixture was concentrated under reduced pressure,taken up in MeOH, filtered, and purified by HPLC Method B. Fractionscontaining product were concentrated under reduced pressure. Thematerial was repurified by HPLC Method A to give the title compound, asa TFA salt, as a pale yellow solid (5.4 mg, 8.9%). ¹H NMR (500 MHz,methanol-d4, mixture of rotamers) δ ppm 1.31 (m, 6H), 1.45 (d, J=11.7Hz, 1H), 1.67 (m, 2H), 2.00 (m, 1H), 2.11 (m, 1H), 2.19 (s, 1.1H), 2.21(s, 1.9H), 2.80 (m, 4H), 3.53 (m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86(t, J=5.9 Hz, 0.7H), 4.11 (m, 1H), 4.60 (s, 0.7H), 4.64 (s, 1.3H), 5.53(m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]⁺ 462.5.

EXAMPLE 118(S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carbaldehyde

A solution of(S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(30.5 mg, 0.073 mmol) in THF (364 μL) at room temperature was treatedwith phenyl formate (140 μL, 1.09 mmol). The reaction mixture wasstirred at 60° C. for 1 h. The reaction was purified by HPLC Method Busing a 50% to 80% ACN gradient to give the title compound, as a TFAsalt, as a pale yellow solid (9.4 mg, 23%). ¹H NMR (500 MHz,methanol-d4, mixture of rotamers) δ ppm 1.29 (m, 6H), 1.45 (d, J=12.7Hz, 1H), 1.66 (m, 2H), 2.00 (m, 1H), 2.10 (m, 1H), 2.77 (m, 4H), 3.49(m, 2H), 3.76 (t, J=5.9Hz, 1.4H), 3.82 (t, J=6.1 Hz, 0.6H), 4.12 (m,1H), 4.48 (s, 0.6H), 4.52 (s, 1.4H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50(td, J=8.3, 6.3 Hz, 1H), 8.18 (s, 0.7H), 8.24 (s, 0.3H); ESI-MS m/z[M+H]⁺ 447.90.

EXAMPLE 119(R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carbaldehyde

A solution of(R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(50.5 mg, 0.120 mmol) in THF (602 μL) at room temperature was treatedwith phenyl formate (232 μL, 1.806 mmol). The reaction mixture wasstirred at 60° C. for 15 min. The reaction mixture was removed from heatand allowed to continue stirring at room temperature for 2 h. Thereaction was purified by HPLC Method B using a 50% to 80% ACN gradientto give the title compound, as a TFA salt, as a pale yellow solid (6.0mg, 8.9% yield).¹H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm1.30 (m, 7H), 1.45 (d, J=13.2 Hz, 1H), 1.67 (m, 2H), 2.01 (m, 1H), 2.11(m, 1H), 2.79 (m, 4H), 3.51 (m, 2H), 3.77 (t, J=5.9 Hz, 1.4H), 3.83 (t,J=6.1 Hz, 0.6H), 4.13 (m, 1H), 4.51 (s, 0.6H), 4.56 (s, 1.4H), 5.53 (m,1H), 7.02 (m, 2H), 7.50 (m, 1H), 8.19 (s, 0.7H), 8.24 (s, 0.3H); ESI-MSm/z [M+H]⁺ 447.95.

EXAMPLE 1201-(3-(4-(3-fluorophenylsulfonyl)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

Combined6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine(55 mg, 0.174 mmol), 4-((3-fluorophenyl)sulfonyl)piperidine, HCl (58.3mg, 0.208 mmol)), Pd₂(dba)₃ (8.0 mg, 8.68 μmol), BINAP (16.2 mg, 0.026mmol) and sodium tert-butoxide (66.7 mg, 0.694 mmol) and toluene (868μL). The suspension was heated at 100° C. for 3.5 h then diluted in DMF,filtered through a hydrophilic PTFE 0.45 μm filter (Millipore®Millex-LCR), and purified via HPLC Method A to give6-benzyl-3-(4-((3-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (68 mg) as a yellow film.

To a solution of6-benzyl-3-(4-((3-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (68 mg, 0.107 mmol) in THF (1333 μL) was added Pd(OH)₂ (20 wt%, 22.5 mg, 0.032 mmol). The flask was purged with nitrogen then allowedto stir under an atmosphere of hydrogen (balloon) for 2 h. The reactionmixture was filtered through a hydrophilic PTFE 0.45 μm filter(Millipore® Millex-LCR) and washed with EtOAc. The crude material wasconcentrated in vacuo to give3-(4-((3-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineas a TFA salt (58 mg) as a yellow film.

To a solution of3-(443-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (58 mg, 0.106 mmol) in DCM (1059 μL) at 0° C. was added aceticanhydride (20.0 μL, 0.212 mmol) and pyridine (25.7 μL, 0.318 mmol).After stirring at 0° C. for 30 min, the reaction mixture wasconcentrated in vacuo. The resulting crude material was dissolved in DCMand purified via automated flash silica gel chromatography using agradient of 0% to 100% EtOAc in heptanes to give the title compound(19.2 mg) as a colorless oil. ¹H NMR (500 MHz, methanol-d4) δ ppm0.85-0.94 (m, 3H), 1.21-1.24 (m, 6H), 1.90-1.99 (m, 2H), 2.19 (d, J=13.7Hz, 3H), 2.67-2.76 (m, 3H), 2.81 (t, J=5.9 Hz, 1H), 3.34-3.42 (m, 1H),3.46-3.55 (m, 2H), 3.78 (t, J=6.1 Hz, 1H), 3.84 (t, J=5.9 Hz, 1H), 4.16(td, J=6.5, 3.7 Hz, 1H), 4.49 (d, J=2.4 Hz, 2H), 7.51-7.57 (m, 1H),7.68-7.75 (m, 2H), 7.76-7.80 (m, 1H); ESI-MS m/z [M+H]⁺ 476.90.

EXAMPLE 1211-(2-(isopropylamino)-3-(4-(3-methoxyphenylsulfonyl)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to Example 120 using4-((3-methoxyphenyl)sulfonyl)piperidine, HCl to give the title compoundas a white solid. ¹H NMR (500 MHz, methanol-d4) δ ppm 0.82-0.94 (m, 2H),1.21-1.24 (m, 6H), 1.87-1.98 (m, 4H), 2.19 (d, J=13.2 Hz, 3H), 2.66-2.75(m, 3H), 2.81 (t, J=6.1 Hz, 1H), 3.46-3.54 (m, 2H), 3.78 (t, J=5.9 Hz,1H), 3.84 (t, J=5.9 Hz, 1H), 3.91 (s, 3H), 4.15 (dd, J=10.7, 4.4 Hz,1H), 4.46-4.50 (m, 2H), 7.29-7.34 (m, 1H), 7.42-7.44 (m, 1H), 7.48-7.52(m, 1H), 7.56-7.61 (m, 1H); ESI-MS m/z [M+H]⁺ 488.90.

EXAMPLE 1221-(3-(4-((2-fluorophenyl)sulfonyl)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

The title compound was prepared in a manner similar to Example 120 using4-((2-fluorophenyl)sulfonyl)piperidine to give the title compound, as aTFA salt, as a pale yellow solid (26.6 mg, 28.9% over two steps, mixtureof rotamers). ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.8 Hz, 6H),1.95 (m, 4H), 2.07 (app d, 3H), 2.65 (m, 4H), 3.49 (m, 3H), 3.69 (m,2H), 4.13 (m, 1H), 4.37 (app d, 2H), 5.69 (br s, 1H), 7.52 (m, 2H), 7.87(m, 2H); ESI-MS m/z [M+H]⁺ 476.00.

EXAMPLE 1231-(3-(4-(4-fluorophenylsulfonyl)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to Example 120 using4-((4-fluorophenyl)sulfonyl)piperidine, HCl to give the title compoundas a colorless oil. ¹H NMR (500 MHz, methanol-d4) δ ppm 0.90 (d, J=6.8Hz, 1H), 1.20-1.24 (m, 6H), 1.90-1.99 (m, 2H), 1.99-2.06 (m, 2H), 2.19(d, J=13.7 Hz, 3H), 2.67-2.76 (m, 3H), 2.82 (t, J=5.9 Hz, 1H), 3.45-3.55(m, 2H), 3.79 (t, J=5.9 Hz, 1H), 3.84 (t, J=5.9 Hz, 1H), 4.12-4.20 (m,1H), 4.49 (s, 2H), 4.58 (s, 1H), 7.42 (td, J =8.7, 1.7 Hz, 2H),7.97-8.02 (m, 2H); ESI-MS m/z [M+H]⁺ 476.90.

EXAMPLE 1243-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carbaldehyde

A mixture of3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amineTFA salt (36 mg, 0.058 mmol), Cs₂CO₃ (66.0 mg, 0.203 mmol), anddifluoroiodomethane (0.051 mL, 0.579 mmol) in DMA (0.5 mL) was heated ina microwave on high absorbance for 15 min at 50° C. The resulting crudematerial was filtered, rinsed with DMSO (2×0.5 mL), and purified by HPLCMethod B using a 30% to 70% ACN gradient to give the title compound as aTFA salt (11.2 mg, 35.5%) as a yellow solid. ¹H NMR (500 MHz,methanol-d₄) δ ppm 1.29 (d, J=6.4 Hz, 6H), 1.90-2.01 (m, 2H), 2.07-2.18(m, 2H), 2.78-2.89 (m, 2H), 3.02-3.10 (m, 2H), 3.39-3.45 (m, 2H),3.76-3.86 (m, 2H), 4.14 (quin, J=6.4 Hz, 1H), 4.46-4.49 (m, 3H),6.85-6.91 (m, 1H), 6.95-7.01 (m, 1H), 7.14-7.21 (m, 1H), 8.16-8.27 (m,1H); ESI-MS m/z [M+H]⁺ 432.4.

EXAMPLE 1251-(3-(4-(2-fluoro-4-methoxyphenylsulfonyl)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[4,3-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to Example 120 using4-((2-fluoro-4-methoxyphenyl)sulfonyl)piperidine, HCl to give the titlecompound as a colorless oil. ¹H NMR (500 MHz, methanol-d4) δ ppm0.87-0.90 (m, 2H), 1.23 (dd, J=6.8, 1.0 Hz, 6H), 1.95-2.02 (m, 3H), 2.19(d, J=12.2 Hz, 3H), 2.69-2.79 (m, 3H), 2.82 (t, J=5.9 Hz, 1H), 3.35-3.42(m, 1H), 3.52 (td, J=8.3, 4.4 Hz, 2H), 3.79 (t, J=5.9 Hz, 1H), 3.85 (t,J=6.1 Hz, 1H), 3.93 (s, 3H), 4.17 (dtt, J=9.8, 6.4, 3.3 Hz, 1H), 4.50(s, 2H), 6.95-7.02 (m, 2H), 7.78-7.84 (m, 1H); ESI-MS m/z [M+H]⁺ 506.90.

EXAMPLE 126(S)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((1-methoxypropan-2-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

A solution of(S)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (127.7 mg, 0.200 mmol) in THF (2.00 mL) at room temperature wastreated with Pd(OH)₂ (20 wt %, 42.2 mg, 0.060 mmol). Hydrogen gas(balloon) was bubbled through the reaction mixture for 5 min. The ventneedle was removed and the reaction mixture was stirred under hydrogenatmosphere for 1 h. The reaction mixture was opened to air and wasfiltered through a pad of Celite™, eluting with EtOAc and MeOH. Thefiltrate was concentrated under reduced pressure to give(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine,as a TFA salt, as a yellow oil, which was carried forward withoutadditional purification. ESI-MS m/z [M+H]⁺ 434.5.

A solution of(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt in DCM (2.009 mL) at 0° C. was treated with pyridine (0.049 mL,0.603 mmol), followed by acetic anhydride (0.038 mL, 0.402 mmol). Thereaction mixture was stirred for 1 h 30 min at 0° C. The reactionmixture was concentrated under reduced pressure and taken up in MeOH,filtered through a Millipore® 0.45 μm syringe filter, and purified byHPLC Method A to give the title compound, as a TFA salt, as ayellow-orange semisolid (46.7 mg, 39.4% over two steps). ¹H NMR (500MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (m, 3H), 1.95 (m, 2H),2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.79 (app t, 0.7H), 2.84(app t, 1.3H), 3.05 (m, 2H), 3.39 (m, 3H), 3.43 (m, 2H), 3.51 (dt,J=5.5, 3.5 Hz, 2H), 3.82 (app t, 1.3H), 3.86 (app t, 0.7H), 4.25 (m,1H), 4.49 (m, 1H), 4.57 (s, 0.7H), 4.60 (s, 1.3H), 6.88 (m, 1H), 6.99(ddd, J=11.2, 8.3, 2.9 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z[M+H]⁺ 476.00.

EXAMPLE 127(R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((1-methoxypropan-2-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

A solution of(R)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (161.4 mg, 0.253 mmol) in THF (2.53 mL) was treated withPd(OH)₂ (20 wt %, 53.3 mg, 0.076 mmol). Hydrogen gas (balloon) wasbubbled through the reaction mixture for 5 min. The vent needle wasremoved and the reaction mixture was allowed to stir under hydrogenatmosphere at room temperature for 2 h. The reaction mixture was openedto air and filtered through a pad of Celite™, eluting with MeOH andEtOAc. The filtrate was collected and concentrated under reducedpressure to give(R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine,as a TFA salt, as a yellow oil, which was carried forward withoutadditional purification. ESI-MS m/z [M+H]⁺ 434.5.

A solution of(R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt in DCM (2.539 mL) at 0° C. was treated with pyridine (0.062 mL,0.762 mmol), followed by acetic anhydride (0.048 mL, 0.508 mmol). Thereaction mixture was stirred at 0° C. for 1 h 30 min. The reactionmixture was concentrated under reduced pressure and taken up in MeOH,filtered through a 0.45 μm Millipore® syringe filter, and purified byHPLC Method A to give the title compound, as a TFA salt, as a yellowsemisolid (41.4 mg, 27.7% over two steps). ¹H NMR (500 MHz, methanol-d4,mixture of rotamers) δ ppm 1.29 (m, 3H), 1.95 (m, 2H), 2.13 (m, 2H),2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.74 (t, J=5.9 Hz, 0.7H), 2.84 (app t,1.3H), 3.09 (m, 2H), 3.38 (m, 3H), 3.47 (m, 4H), 3.82 (t, J=6.1 Hz,1.3H), 3.86 (t, J=5.9 Hz, 0.7H), 4.26 (m, 1H), 4.49 (m, 1H), 4.59 (br s,0.7H), 4.62 (s, 1.3H), 6.87 (m, 1H), 6.98 (ddd, J=11.3, 8.7, 2.9 Hz,1H), 7.27 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 476.00.

EXAMPLE 1281-(3-(cyclobutylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

A solution ofN-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (144 mg, 0.272 mmol) in DCM (2.72 mL) at 0° C. was treated withpyridine (66.0 μL, 0.816 mmol), followed by acetic anhydride (51.3 μL,0.544 mmol). The reaction mixture was stirred at 0° C. for 2 h. Thereaction mixture was concentrated under reduced pressure and taken up inMeOH, filtered through a 0.45 μm Millipore® syringe filter, and purifiedvia HPLC Method A to give the title compound, as a TFA salt, as a yellowsolid (74.9 mg, 48.2%). ¹H NMR (500 MHz, methanol-d4, mixture ofrotamers) δ ppm 1.82 (m, 2H), 1.97 (m, 2H), 2.11 (m, 4H), 2.19 (s,1.1H), 2.21 (s, 1.9H), 2.45 (m, 2H), 2.73 (t, J=5.9 Hz, 0.7H), 2.84 (t,J=5.9 Hz, 1.3H), 3.11 (m, 2H), 3.47 (m, 2H), 3.81 (t, J=5.9 Hz, 1.3 H),3.85 (t, J=5.9 Hz, 0.7H), 4.40 (m, 1H), 4.49 (m, 1H), 4.59 (s, 0.7H),4.63 (s, 1.3H), 6.87 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.17(td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 458.00.

EXAMPLE 128A1-(3-(cyclobutylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To a solution ofN-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine(12.0 g, 29 2 mmol) in acetone (200 mL) and dioxane (300 mL) was addedAc₂O (30 mL, 318 mmol) and Pd/C (1.80 g, 16.91 mmol). The reaction wasthen stirred at 60° C. under H₂ atmosphere (345 kPa) for 72 h. Then themixture was filtered through a pad of Celite™, washing with EtOAc. Thereaction solution was diluted with EtOAc (50 mL) and poured intosaturated aqueous NaHCO₃ (50 mL), then washed with brine (2×30 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was recrystallized with PE/EtOAc, lyophilized and washed withPE/EtOAc (5:1) to give pure title compound (6.1 g). ¹H NMR (500 MHz,DMSO-d₆, mixture of rotamers) δ ppm 1.57-1.74 (m, 2H), 1.85-1.95 (m,2H), 1.97-2.08 (m, 4H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.19-2.30 (m,2H), 2.58 (t, J=5.9 Hz, 0.9H), 2.71 (t, J=5.9 Hz, 1.1H), 2.88 (t, J=10.5Hz, 2H), 3.23-3.33 (m, 2H), 3.70 (dt, J=11.7, 5.9 Hz, 2H), 4.32-4.47 (m,3H), 4.52 (tt, J=8.1, 3.8 Hz, 1H), 6.05 (d, J=7.8 Hz, 0.4H), 6.08 (d,J=8.3 Hz, 0.6H 6.96-7.07 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]⁺458.00.

EXAMPLE 129(S)-1-(3-(sec-butylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

A solution of(S)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (212.2 mg, 0.341 mmol) in THF (3.4 mL) was treated with Pd(OH)₂(20 wt %, 71.9 mg, 0.102 mmol). Hydrogen gas (balloon) was bubbledthrough the reaction mixture for 5 min. The vent needle was removed andthe reaction mixture was stirred at room temperature under hydrogenatmosphere for 3 h. The reaction mixture was opened to air and filteredthrough a pad of Celite™, eluting with EtOAc and MeOH. The filtrate wascollected and concentrated under reduced pressure to give(S)-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineas a TFA salt (169.0 mg) as a yellow oil, which was carried forwardwithout additional purification. ESI-MS m/z [M+H]⁺ 418.5.

A solution of(S)-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (169.0 mg) in DCM (3.18 mL) at 0° C. was treated with pyridine(0.077 mL, 0.954 mmol), followed by acetic anhydride (0.060 mL, 0.636mmol). The reaction mixture was stirred for 1 h. The reaction mixturewas concentrated under reduced pressure. The residue was taken up inMeOH, filtered through a Millipore® 0.45 μm syringe filter, and purifiedby HPLC Method A to give the title compound, as a TFA salt, as a yellowsemisolid (84.9 mg, 43.4% over two steps). ¹H NMR (500 MHz, methanol-d4,mixture of rotamers) δ ppm 0.98 (m, 3H), 1.27 (m, 3H), 1.68 (m, 2H),1.97 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.74 (td,J=5.9, 1.5 Hz, 0.7H), 2.84 (td, J=5.9, 1.5 Hz, 1.3H), 3.11 (m, 2H), 3.45(m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.50(m, 1H), 4.61 (d, J=3.9 Hz, 0.7H), 4.64 (s, 1.3H), 6.87 (m, 1H), 6.97(ddd, J=11.3, 8.7, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z[M+H]⁺ 460.00.

EXAMPLE 130(R)-1-(3-(sec-butylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

A solution of(R)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (174.6 mg, 0.281 mmol) in THF (2.81 mL) was treated withPd(OH)₂ (20 wt %, 59.2 mg, 0.084 mmol). Hydrogen gas (balloon) wasbubbled through the reaction mixture for 5 min. The vent needle wasremoved and the reaction was allowed to stir at room temperature underhydrogen atmosphere for 1 h. The reaction mixture was opened to air andfiltered through a pad of Celite™, eluting with EtOAc/MeOH. The filtratewas collected and concentrated under reduced pressure to give(R)-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineas a TFA salt (136.4 mg) as a yellow oil, which was carried forwardwithout additional purification. ESI-MS m/z [M+H]⁺ 418.5.

A solution of(R)-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineTFA salt (136.4 mg) in DCM (2.57 mL) at 0° C. was treated with pyridine(0.062 mL, 0.770 mmol), followed by acetic anhydride (0.048 mL, 0.513mmol). The reaction mixture was stirred for 1 h. The reaction mixturewas concentrated under reduced pressure. The residue was taken up inMeOH, filtered through a Millipore® 0.45 μm syringe filter, and purifiedby HPLC Method A to give title compound, as a TFA salt, as a yellowsolid (52.0 mg, 32.2% over two steps).¹H NMR (500 MHz, methanol-d4) δppm 0.98 (m, 3H), 1.26 (m, 3H), 1.67 (m, 2H), 1.96 (m, 2H), 2.13 (m,2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.73 (td, J=5.9, 1.5 Hz, 0.7H),2.84 (td, J=5.9, 1.5 Hz, 1.3H), 3.08 (m, 2H), 3.43 (m, 2H), 3.82 (t,J=5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.49 (m, 1H), 4.59 (m,0.7H), 4.63 (s, 1.3H), 6.87 (m, 1H), 6.98 (ddd, J=11.3, 8.4, 3.2 Hz,1H), 7.17 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 460.0.

EXAMPLE 1311-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-1-one

To a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(50 mg, 0.124 mmol) in DCM (1.24 mL) at 0° C. was added DIPEA (32.5 μL,0.186 mmol) and propionic anhydride (19.2 μL, 0.149 mmol). The resultingsolution was stirred at this temperature for 2 h. Purification by silicagel column chromatography using 0% to 100% EtOAc in heptanes gave thetitle compound as a white solid (53 mg, 93%). ¹H NMR (400 MHz,methanol-d₄, mixture of rotamers) δ ppm ¹H NMR (400 MHz, methanol-d₄,mixture of rotamers) δ ppm 1.10-1.20 (m, 3H), 1.25 (d, J=6.8 Hz, 3H),1.26 (d, J=6.8 Hz, 3H), 1.90-2.00 (m, 2H), 2.09-2.18 (m, 2H), 2.47-2.58(m, 2H), 2.72 (t, J=5.9 Hz, 0.8 H), 2.81 (t, J=5.9 Hz, 1.2H), 2.92-3.01(m, 2H), 3.81 (t, J=5.9 Hz, 1.2H), 3.87 (t, J=6.1 Hz, 0.8H), 4.13-4.21(m, 1H), 4.46 (tt, J=7.5, 3.7 Hz, 1H), 4.55 (s, 0.8H), 4.56 (s, 1.2H),6.85-6.92 (m, 1H), 6.99 (m, 1H), 7.18 (m, 1H); ESI-MS m/z [M+Na]⁺ 482.9.

EXAMPLE 132 Methyl2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxylate

To a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(45.6 mg, 0.113 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM(0.75 mL) was added methyl carbonochloridate (0.013 mL, 0.170 mmol) at0° C. The reaction mixture was stirred at 0° C. for 1 hr, warmed to 23°C., and concentrated via rotary evaporation. The resulting crudematerial was partitioned between EtOAc and H2O. The organic phase waswashed with brine, dried over Na₂SO₄, filtered, rinsed with EtOAc, andconcentrated via rotary evaporation. The crude material was dissolved intoluene (0.5 mL) and purified via medium pressure chromatography using a2% to 80% gradient eluant of EtOAc in heptane on a 12 g silica gelcolumn (Single Step™) to give the title compound (48.7 mg, 93%) as awhite foam. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17-1.19 (m, 6H), 1.80-1.94(m, 2H), 2.06 (ddd, J=9.5, 5.9, 3.2 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H),2.82-2.94 (m, 2H), 3.19-3.31 (m, 2H), 3.64 (s, 3H), 3.64-3.69 (m, 2H),4.07-4.17 (m, 1H), 4.35 (br s, 2H), 4.51 (tt, J=8.1, 3.9 Hz, 1H), 5.53(d, J=8.3 Hz, 1H), 7.01 (dddd, J=9.3, 8.1, 3.2, 1.5 Hz, 1H), 7.26-7.35(m, 2H); ESI-MS m/z [M+H]⁺ 461.9.

EXAMPLE 1332-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(2-fluoroethyl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

To a suspension of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(98.4 mg, 0.244 mmol) and K₂CO₃ (135 mg, 0.976 mmol) in acetone (4.0 mL)was added 1-bromo-2-fluoroethane (0.020 mL, 0.268 mmol) at 23° C. Thereaction mixture was stirred at 50° C. for 1 hr. The reaction mixturewas cooled to 23° C., an additional portion of 1-bromo-2-fluoroethane(8.2 μL, 0.110 mmol) was added, and the reaction mixture was heated foran additional 1.5 hr at 50° C., cooled to 23° C., and concentrated viarotary evaporation. The resulting crude material was reconstituted inDMSO, filtered, rinsed with DMSO, and purified by HPLC Method B using a30% to 70% ACN gradient to give the title compound (42 mg, 38.3%) as alight yellow oil. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers) δ ppm1.17 (d, J=6.8 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.62-2.69(m, 2H), 2.73-2.80 (m, 3H), 2.81-2.91 (m, 3H), 3.20-3.29 (m, 2H), 3.48(s, 2H), 4.04-4.12 (m, 1H), 4.47-4.54 (m, 1H), 4.56 (t, J=4.9 Hz, 1H),4.66 (t, J=4.9 Hz, 1H), 5.38 (d, J=7.8 Hz, 1H), 6.98-7.05 (m, 1H),7.26-7.34 (m, 2H); ESI-MS m/z [M+H]⁺ 450.0.

EXAMPLE 1341-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To a pressure reactor charged with a red-orange solution of2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine(0.5 g, 1.255 mmol) in acetone (25 mL) and dioxane (25 mL) was addedpalladium, 10 wt % on activated carbon (0.053 g, 0.502 mmol) as a slurryin dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.179 mL,12.55 mmol) was added at 23° C. The mixture was stirred under hydrogenat 45° C. and 310 kPa for 9.5 hr. The reaction mixture was filteredthrough Celite™, rinsed with EtOAc, and concentrated via rotaryevaporation. The crude material was dissolved in toluene (5 mL) andpurified via medium pressure chromatography using a 10% to 100% gradienteluant of EtOAc in heptane on an NH 60 μM size 400 column (ShokoScientific Purif-Pack™) to give the title compound (341 mg, 61.1%) as anoff-white foam. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers) δ ppm1.14-1.19 (m, 6H), 2.08 (s, 1.2H), 2.09 (s, 1.8H), 2.52-2.65 (m, 5H),2.70 (t, J=5.9 Hz, 1H), 2.98 (br s, 4H), 3.58 (s, 2H), 3.70 (dt, J=12.0,5.7 Hz, 2H), 4.00-4.15 (m, 1H), 4.40 (s, 0.8H), 4.43 (s, 1.2H), 5.35 (d,J=7.8 Hz, 0.4H), 5.38 (d, J=8.3 Hz, 0.6H) 7.08 (td, J=8.3, 2.4 Hz, 1H),7.21 (td, J=10.0, 2.4 Hz, 1H), 7.44-7.51 (m, 1H); ESI-MS m/z [M+H]⁺445.0.

EXAMPLE 1351-(3-(cyclobutylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

ToN-cyclobutyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine(0.500 g, 1.218 mmol) in acetone (25 mL) and dioxane (25 mL) was addedpalladium, 10 wt % on activated carbon (0.052 g, 0.487 mmol) as a slurryin dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.144 mL,12.18 mmol) was added at 23° C. The mixture was stirred under hydrogenat 310 kPa for 50 hr at 45° C. The crude mixture was filtered throughCelite™, rinsed with dioxane, and concentrated via rotary evaporation.The crude material was purified via medium pressure chromatography usinga 10% to 100% gradient eluant of EtOAc in heptanes on an NH 60 μM size60 column (Shoko Scientific Purif-Pack™) to give the title compound1-(3-(cyclobutylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone(284 mg, 51.1%) as a yellow foam. ¹H NMR (500 MHz, DMSO-d₆, mixture ofrotamers) δ ppm 1.56-1.72 (m, 2H), 1.97-2.06 (m, 2H), 2.07 (s, 1.3H),2.08 (s, 1.7H), 2.18-2.27 (m, 2H), 2.52-2.66 (m, 4.9H), 2.69 (t, J=5.9Hz, 1.1H), 2.99 (br s, 4H), 3.59 (s, 2H), 3.69 (dt, J=11.5, 6.0 Hz, 2H),4.27-4.46 (m, 3H), 5.89 (d, J=7.3 Hz, 0.4H), 5.93 (d, J=7.8 Hz, 0.6H),7.02-7.13 (m, 1H), 7.17-7.27 (m, 1H), 7.41-7.55 (m, 1H); ESI-MS m/z[M+H]⁺ 457.0.

EXAMPLE 1362-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

To a solution of2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) wasadded methanesulfonyl chloride (10.6 μL, 0.137 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 1 hr and concentrated viarotary evaporation. The resulting crude material was partitioned betweenEtOAc (2 mL) and water (1 mL). The organic phase was washed with brine,dried over Na₂SO₄, filtered, rinsed with EtOAc, and concentrated viarotary evaporation. The crude material was dissolved in EtOAc and MeOH,adsorbed on silica gel (0.75 g), and purified via medium pressurechromatography using a gradient eluant of 50% to 100% EtOAc in heptaneon a 4 g silica gel column (Single Step™) to give the title compound(50.6 mg, 85%) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.12-1.19 (m, 6H), 2.53-2.61 (m, 4H), 2.74 (t, J=5.9 Hz, 2H), 2.97 (s,3H), 3.00 (d, J=7.3 Hz, 4H), 3.44-3.48 (m, 1H), 3.59 (s, 2H), 4.02-4.10(m, 1H), 4.16 (s, 2H), 5.41 (d, J=7.8 Hz, 1H), 7.08 (td, J=8.4, 2.2 Hz,1H), 7.22 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.54 (m, 1H); ESI-MS m/z [M+H]⁺480.9.

EXAMPLE 1371-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-1-one

To a solution of2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) wasadded propionic anhydride (0.019 mL, 0.149 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 1 hr, warmed to 23° C., andconcentrated via rotary evaporation. The resulting crude material waspartitioned between EtOAc and water. The organic phase was washed withbrine, dried over Na₂SO₄, filtered, rinsed with EtOAc, and concentratedvia rotary evaporation. The crude material was dissolved in EtOAc andMeOH, adsorbed on silica gel (0.75 g), and purified via medium pressurechromatography using a 20% to 100% gradient of EtOAc in heptane on a 4 gsilica gel column (Single Step™) to give the title compound (48 mg, 84%yield) as an off-white foam. ¹H NMR (500 MHz, DMSO-d₆, mixture ofrotamers) δ ppm 0.94-1.05 (m, 3H), 1.16-1.18 (m, 6H), 2.41 (quin, J=7.8Hz, 2H), 2.52-2.65 (m, 5H), 2.69 (t, J=5.6 Hz, 1H), 2.98 (br s, 3H),3.58 (s, 2H), 3.70 (t, J=5.9 Hz, 1.1H), 3.73 (t, J=5.9 Hz, 0.9H), 4.03(q, J=7.2 Hz, 2H), 4.06-4.15 (m, 1H), 4.42 (br s, 2H), 5.34 (d, J=7.8Hz, 0.6H), 5.37 (d, J=8.3 Hz, 0.4H), 7.08 (td, J=8.5, 2.4 Hz, 1H), 7.21(td, J=9.9, 2.7 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+F]⁺ 459.0.

EXAMPLE 138 Tert-butyl4-(6-acetyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate

To a pressure reactor charged with a red-orange solution of tert-butyl4-(3-(isopropylamino)pyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate(2.0 g, 5.37 mmol) in acetone (100 mL) and dioxane (100 mL) was addedpalladium, 10 wt % on activated carbon (0.229 g, 2.148 mmol) as a slurryin dioxane (3 mL) under nitrogen. Next, acetic anhydride (5.04 mL, 53.7mmol) was added at 23° C. The mixture was stirred under hydrogen at 310kPa for 17 hr at 45° C. The reaction mixture was filtered throughCelite™, rinsed with dioxane, and concentrated via rotary evaporation.The crude material was purified via medium pressure chromatography using10% to 100% gradient of EtOAc in heptane on an NH 60 μM size 400 column(Shoko Scientific Purif-Pack™) to give the title compound (1.068 g,47.5%) as a yellow foam. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers)δ ppm 1.16-1.21 (m, 6H), 1.42 (s, 9H), 2.08 (s, 1.3H), 2.09 (s, 1.7H),2.58 (t, J=5.9 Hz, 0.9H), 2.70 (t, J=5.6 Hz, 1.1H), 2.87-2.98 (m, 4H),3.51 (br s, 4H), 3.67-3.75 (m, 2H), 4.06-4.15 (m, 1H), 4.41 (s, 1.1H),4.44 (s, 0.9H), 5.50 (d, J=7.8 Hz, 1H), 5.53 (d, J=7.8 Hz, 1H); ESI-MSm/z [M+H]⁺ 419.0.

EXAMPLE 139(1s,3s)-3-((6-acetyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)amino)cyclobutylacetate

To a pressure reactor charged with a red-orange solution of(1s,3s)-3-((2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-yl)amino)cyclobutanol(0.3 g, 0.703 mmol) in acetone (15 mL) and dioxane (15 mL) was addedpalladium, 10 wt % on activated carbon (0.030 g, 0.281 mmol) as a slurryin dioxane (3 mL) under nitrogen. Next, acetic anhydride (0.661 mL, 7.03mmol) was added at 23° C. The reaction mixture was stirred underhydrogen at 310 kPa for 4 days at 45° C. The reaction mixture wasfiltered through Celite™, rinsed with dioxane, and concentrated viarotary evaporation. The crude material was dissolved in toluene (3 mL)and purified via medium pressure chromatography using a gradient eluantof 30% to 100% EtOAc in heptane on a 90 g silica gel column (SingleStep™) to give the title compound (119.7 mg, 33.1%) as a yellow foam. ¹HNMR (500 MHz, DMSO-d₆, mixture of rotamers) δ ppm 1.97-2.00 (m, 3H),2.07 (s, 1.3H), 2.08 (s, 1.7H), 2.10-2.17 (m, 2H), 2.55-2.63 (m, 5H),2.67-2.74 (m, 3H), 2.90-3.10 (m, 4H), 3.59 (s, 2H), 3.66-3.74 (m, 2H),4.02-4.12 (m, 1H), 4.39 (s, 1.1H), 4,42 (s, 0.9H), 4.68 (quind, J=7.3,3.4 Hz, 1H), 6.11 (d, J=7.8 Hz, 0.6H), 6.15 (d, J=7.8 Hz, 0.4H), 7.08(td, J=8.5, 2.4 Hz, 1H), 7.19-7.24 (m, 1H), 7.45-7.51 (m, 1H); ESI-MSm/z [M+H]⁺ 515.0.

EXAMPLE 1401-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(((1s,3s)-3-hydroxycyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To a solution of(1s,3s)-3-((6-acetyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)amino)cyclobutylacetate (94.8 mg, 0.184 mmol) in MeOH (2 mL) was added sodium methoxide(5.1 μL, 0.028 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h,concentrated via rotary evaporation at 30° C., re-constituted with MeOH(2 mL), cooled to 0° C., and quenched with HOAc (0.005 mL). The reactionmixture was concentrated via rotary evaporation, partitioned betweenEtOAc (4 mL) and saturated NH₄Cl (1 mL), and the layers were separated.The organic phase was washed with brine (1 mL), dried over Na₂SO₄,filtered, rinsed with EtOAc, and dried in vacuo to give the titlecompound (79.3 mg, 91%) as a yellowish-orange foam. ¹H NMR (500 MHz,DMSO-d₆, mixture of rotamers) δ ppm 1.80-1.88 (m, 2H), 2.07 (s, 1.3H),2.08 (s, 1.7H), 2.54-2.64 (m, 7H), 2.69 (t, J=5.9 Hz, 1H), 2.99 (br s,4H), 3.59 (s, 2H), 3.69 (dt, J=11.5, 6.0 Hz, 2H), 3.77-3.91 (m, 2H),4.38 (s, 1.1H), 4.41 (s, 0.9H), 4.95-5.00 (m, 1H), 5.82 (d, J=7.3 Hz,1H), 5.85 (d, J=7.8 Hz, 1H) 7.08 (td, J=8.4, 2.2 Hz, 1H), 7.19-7.24 (m,1H), 7.45-7.51 (m, 1H); ESI-MS m/z [M+H]⁺ 473.0.

EXAMPLE 1411-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-d3-ethan-1-one

To a solution of2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(2.4 g, 5.95 mmol) and DIPEA (1.56 mL, 8.92 mmol) in DCM (59.5 mL) at 0°C. was added acetyl chloride-d3 (0.42 mL, 5.95 mmol) dropwise. Theresulting solution was stirred at this temperature for 1 h. Afterconcentration, purification with silica gel column chromatography using30% to 100% EtOAc in heptanes gave the title compound (1.89 g, 70.8%).¹H NMR (400 MHz, DMSO-d₆, mixture of rotamers) δ ppm 1.19 (d, J=6.4 Hz,2.7H), 1.21 (d, J=6.4 Hz, 3.3H), 1.82-1.92 (m, 2H), 2.03-2.11 (m, 2H),2.59 (t, J=5.9 Hz, 0.9H), 2.71 (t, J=5.9 Hz, 1.1H), 2.87 (m, 2H),3.22-3.30 (m, 2H), 3.67-3.74 (m, 2H), 4.06-4.16 (m, 1H), 4.41 (s, 1.1H),4.43 (s, 0.9H), 4.51 (m, 1H), 5.50 (d, J=8.3 Hz, 1.1H), 5.54 (d, J=7.8Hz, 0.9H), 6.92-7.06 (m, 1H), 7.21-7.35 (m, 2H); ESI-MS m/z [M+H]⁺449.0.

EXAMPLE 142(1s,3s)-3-((6-acetyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)amino)cyclobutylacetate

To a pressure reactor charged with a red-orange solution of(1s,3s)-3-((2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-yl)amino)cyclobutanol(0.355 g, 0.831 mmol) in acetone (15 mL) and dioxane (15 mL) was addedpalladium, 10 wt % on activated carbon (0.035 g, 0.332 mmol) as a slurryin dioxane (3 mL) under nitrogen. Next, acetic anhydride (0.780 mL, 8.31mmol) was added at 23° C. The reaction mixture was stirred underhydrogen at 310 kPa for 48 hr at 45° C. Additional portions ofpalladium, 10 wt % on activated carbon and acetic anhydride (0.156 mL,1.661 mmol) were added to the pressure reactor and the reaction mixturewas stirred under hydrogen at 310 kPa for an additional 4 days at 45° C.The reaction mixture was filtered through Celite™, rinsed with dioxane,and concentrated via rotary evaporation. The crude material wasdissolved in toluene (3 mL) and purified via medium pressurechromatography using a gradient eluant of 30% to 100% EtOAc in heptaneon a 90 g silica gel column (Single Step™) to give the title compound asa HOAc salt. The HOAc salt was dissolved in MeOH, passed through a 200mg VariPure™ IPE cartridge (HCO₃MP) to remove HOAc, and the cartridgewas rinsed with MeOH. The filtrate was concentrated via rotaryevaporation and dried in vacuo to give the title compound (165 mg,38.5%) as a yellow foam. ¹FINMR (500 MHz, DMSO-d₆, mixture of rotamers)δ ppm 1.86-1.96 (m, 2H), 1.98-2.01 (m, 3H), 2.01-2.08 (m, 2H), 2.08 (s,1.3H), 2.09 (s, 1.7H), 2.11-2.20 (m, 2H), 2.59 (t, J=5.9 Hz, 0.9H),2.67-2.77 (m, 3.1H), 2.83-2.91 (m, 2H), 3.29 (d, J=10.3 Hz, 2H), 3.70(dt, J=11.4, 5.8 Hz, 2H), 4.06-4.13 (m, 1H), 4.40 (s, 1H), 4.43 (s, 1H),4.52 (dt, J=8.2, 4.0 Hz, 1H), 4.69 (td, J=7.3, 2.9 Hz, 1H), 6.24 (d,J=7.3 Hz, 0.6H), 6.28 (d, J=7.8 Hz, 0.4H), 6.98-7.05 (m, 1H), 7.26-7.34(m, 2H); ESI-MS m/z [M+F]⁺ 516.0.

EXAMPLE 1431-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methylpropan-1-one

To a solution of2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine(50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) wasadded isobutyryl chloride (0.013 mL, 0.124 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 1 h, warmed to 23° C. and stirred foran additional 15.5 h. The reaction mixture was concentrated via rotaryevaporation and partitioned between EtOAc (4 mL) and NH₄Cl (2 mL). Thelayers were separated and the organic phase was washed with brine (2mL), dried over Na₂SO₄, filtered, rinsed with EtOAc, and concentratedvia rotary evaporation. The crude material was dissolved in EtOAc andMeOH, adsorbed on silica gel (0.25 g), and purified via medium pressurechromatography using a 50% to 100% gradient of EtOAc in heptane on a 4 gsilica gel column (Single Step™) to give the title compound (39.3 mg,66.9%) as a yellow foam. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers)δ ppm 0.99 (d, J=6.8 Hz, 2.7H), 1.03 (d, J=6.8 Hz, 3H), 1.11-1.22 (m,6H), 2.58 (br s, 3.8H), 2.69 (t, J=5.4 Hz, 1.2H), 2.88-3.13 (m, 5H),3.58 (s, 2H), 3.75 (dt, J=10.9, 5.6 Hz, 2H), 4.05-4.17 (m, 1H), 4.41 (s,1.1H), 4.49 (s, 0.9H), 5.29-5.42 (m, 1H), 7.08 (td, J=8.5, 2.4 Hz, 1H),7.21 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+F]⁺473.0.

EXAMPLE 1441-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(((1s,3s)-3-hydroxycyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To a solution of(1s,3s)-3-((6-acetyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)amino)cyclobutylacetate (146.5 mg, 0.284 mmol) in MeOH (3 mL) was added sodium methoxide(7.89 μL, 0.043 mmol) at 0° C. The reaction was stirred at 0° C. for 1h, concentrated via rotary evaporation at 30° C., re-constituted withMeOH (2 mL), cooled to 0° C., and quenched with HOAc (0.005 mL). Thereaction mixture was concentrated via rotary evaporation, partitionedbetween EtOAc (6 mL) and saturated NH₄Cl (4 mL), and the layers wereseparated. The organic phase was washed with brine (2 mL), dried overNa₂SO₄, filtered, rinsed with EtOAc, and dried in vacuo to give thetitle compound (119.5 mg, 89%) as a yellow oil. ¹H NMR (500 MHz,DMSO-d₆, mixture of rotamers) δ ppm 1.84-1.93 (m, 4H), 2.04-2.11 (m,5H), 2.56-2.65 (m, 2.9H), 2.71 (t, J=5.9 Hz, 1.1H), 2.87 (t, J=10.3 Hz,2H), 3.27 (dd, J=8.1, 4.2 Hz, 2H), 3.70 (dt, J=11.5, 6.0 Hz, 2H),3.79-3.91 (m, 2H), 4.40 (s, 1.1H), 4.42 (s, 0.9H), 4.51 (tt, J=8.2, 4.0Hz, 1H), 4.99-5.04 (m, 1H), 5.99 (d, J=7.3 Hz, 1.1H), 6.03 (d, J=7.8 Hz,1H), 6.99-7.04 (m, 1H), 7.26-7.33 (m, 2H); ESI-MS m/z [M+H]⁺ 473.9.

EXAMPLE 1451-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(((1r,3r)-3-fluorocyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To a solution of1-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-34(1s,3s)-3-hydroxycyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone(25 mg, 0.053 mmol) in DCM (1 mL) was added DAST (9.1 μL, 0.069 mmol) asa solution in DCM (0.5 mL) at −78° C. during 2 min. The reaction wasstirred at −78° C. for 2 h, warmed slowly to 23° C., and stirred for anadditional 14.5 h at 23° C. The reaction mixture was cooled to −78° C.and an additional portion of DAST (0.021 mL, 0.159 mmol) was added tothe mixture. The reaction mixture was warmed slowly to 23° C. andstirred for an additional 24 hr, cooled to 0° C. and quenched with water(5 mL). The crude product was extracted with EtOAc (2×10 mL), theorganic extracts were combined, dried over Na₂SO₄, filtered, rinsed withEtOAc, and dried in vacuo. The resulting crude material wasre-constituted in DMSO (0.5 mL), rinsed with DMSO (2×0.25 mL), andpurified by HPLC Method B using a 20% to 50% ACN gradient to give thetitle compound as a TFA salt (1.2 mg, 3.8%) as an off-white solid. ¹HNMR (500 MHz, methanol-d₄, mixture of rotamers) δ ppm 2.18-2.23 (m, 3H),2.36-2.50 (m, 2H), 2.55-2.69 (m, 2H), 2.73 (t, J=5.4 Hz, 0.9H),2.80-2.86 (m, 1.1H), 3.26-3.30 (m, 4H), 3.47-3.72 (m, 4H), 3.81 (t,J=5.6 Hz, 1.1H), 3.87 (t, J=6.1 Hz, 0.9H), 4.49 (s, 2H), 4.55-4.59 (m,2H), 4.83 (s, 2H), 5.15-5.21 (m, 0.6H), 5.26-5.33 (m, 0.4H), 7.65-7.71(m, 1H); ESI-MS m/z [M+H]⁺ 474.9.

EXAMPLE 1464-((4-(6-acetyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperazin-1-yl)methyl)-3-fluorobenzonitrile

Combined1-(3-(isopropylamino)-2-(piperazin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanonehydrochloride (132.2 mg, 0.218 mmol) and 3-fluoro-4-formylbenzonitrile(32.6 mg, 0.218 mmol) in DCE (1 mL) and added sodiumtriacetoxyhydroborate (64.8 mg, 0.306 mmol) at 23° C. The reactionmixture was stirred at 23° C. for 43 h. An additional portion of sodiumtriacetoxyhydroborate (64.8 mg, 0.306 mmol) was added to the reactionmixture and the mixture was stirred for an additional 24 h at 23° C. Theresulting residue was diluted with DCE (1 mL), filtered, rinsed withMeOH, and concentrated via rotary evaporation. The resulting crudematerial was reconstituted in DMSO (1 mL), filtered, rinsed with DMSO(2×0.5 mL), and purified by HPLC Method A to give the title compound asa TFA salt (28.0 mg, 22.68%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆, mixture of rotamers) δ ppm 1.13-1.28 (m, 6H), 2.08 (s, 1.3H),2.09 (s, 1.7H), 2.59 (t, J=5.9 Hz, 0.9H), 2.67-2.75 (m, 1.1H), 2.90-3.21(m, 2H), 3.28-3.63 (m, 6H), 3.67-3.77 (m, 2H), 4.06-4.19 (m, 1H), 4.42(s, 1.1H), 4.45 (s, 0.9H), 4.50 (br s, 2H), 5.68-5.77 (m, 1H), 7.83-7.87(m, 1H), 7.87-7.92 (m, 1H), 8.01-8.22 (m, 1H), 10.22 (br s, 1H); ESI-MSm/z [M+F]⁺ 452.0.

EXAMPLE 147(1r,3r)-3-((6-acetyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)amino)cyclobutylacetate

To a pressure reactor charged with an orange solution of(1r,3r)-3-((2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-yl)amino)cyclobutanol(0.8 g, 1.872 mmol) in acetone (30 mL) and dioxane (30 mL) was addedpalladium, 10 wt % on activated carbon (0.100 g, 0.936 mmol) as a slurryin dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.758 mL,18.72 mmol) was added at 23° C. The mixture was stirred under hydrogenat 310 kPa for 3 days at 45° C. Additional portions of palladium, 10 wt% on activated carbon (0.100 g, 0.936 mmol) and acetic anhydride (0.352mL, 3.74 mmol) were added to the reactor and the mixture was stirredunder hydrogen at 45 kPa for 2 additional days at 45° C. The reactionmixture was filtered through Celite™, rinsed with dioxane, andconcentrated via rotary evaporation. The crude material was dissolved intoluene (2 mL) and purified via medium pressure chromatography using a30% to 100% gradient of EtOAc in heptane on a 160 g silica gel column(Single Step™) to give the title compound (270 mg, 28.0%) as anoff-white solid. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers) δ ppm1.83-1.97 (m, 2H), 2.03 (s, 3H), 2.04-2.12 (m, 5H), 2.33-2.41 (m, 2H),2.41-2.49 (m, 2H), 2.59 (t, J=5.9 Hz, 0.9H), 2.71 (t, J=5.6 Hz, 1.1H),2.89 (t, J=10.0 Hz, 2H), 3.20-3.34 (m, 4H), 3.56-3.79 (m, 2H), 4.40 (s,1.1H), 4.43 (s, 0.9H), 4.47-4.59 (m, 2H), 5.05 (td, J=6.9, 3.2 Hz, 1H),6.24 (d, J=6.8 Hz, 0.6 H), 6.27 (d, J=6.8 Hz, 0.4H), 6.94-7.11 (m, 1H),7.22-7.43 (m, 2H); ESI-MS m/z [M+F]⁺ 515.9.

EXAMPLE 1481-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(((1r,3r)-3-hydroxycyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To an off-white suspension of(1r,3r)-3-((6-acetyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)amino)cyclobutylacetate (108 mg, 0.209 mmol) in MeOH (2 mL) was added sodium methoxide(5.8 μL, 0.031 mmol) at 23° C. The reaction was stirred at 23° C. for 15min, concentrated via rotary evaporation at 30° C., re-constituted withMeOH (2 mL), cooled to 23° C., and quenched with HOAc (0.010 mL). Thereaction mixture was concentrated via rotary evaporation, partitionedbetween EtOAc (6 mL) and saturated NH₄Cl (4 mL), and the layers wereseparated. The organic phase was washed with brine (2 mL), dried overNa₂SO₄, filtered, rinsed with EtOAc, and dried in vacuo to give thetitle compound (99 mg, 100%) as a yellow foam. ¹H NMR (500 MHz, DMSO-d₆,mixture of rotamers) δ ppm 1.87-1.93 (m, 2H), 2.00-2.12 (m, 5H),2.12-2.20 (m, 2H), 2.21-2.32 (m, 2H), 2.55-2.62 (m, 0.9H), 2.71 (t,J=5.1 Hz, 1.1H), 2.88 (t, J=10.0 Hz, 2H), 3.28 (br s, 2H), 3.63-3.80 (m,2H), 4.29 (d, J=3.9 Hz, 1H), 4.40 (s, 1.1H) 4.43 (s, 0.9H), 4.47-4.62(m, 1H), 4.95 (d, J=4.9 Hz, 1H), 5.99 (d, J=6.3 Hz, 1H), 6.03 (d, J=6.8Hz, 1H), 6.96-7.08 (m, 1H), 7.23-7.36 (m, 2H); ESI-MS m/z (M+H)⁺ 474.0.

EXAMPLE 149(S)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

To a solution of(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine(2.0 g, 4.68 mmol) in dioxane:acetone (50 ml; 1.5:1) was added Ac₂O (4.8mL, 50.9 mmol) and Pd/C (400 mg, 3.76 mmol); then, the reaction wasstirred at 60° C. under H₂ atmosphere (345 kPa) for 72 h. The mixturewas filtered through a pad of Celite™ and washed with EtOAc. Thereaction solution was diluted with EtOAc (50 mL) and poured into sat.aqueous NaHCO₃ (50 ml), then washed with brine (2×30 mL). The organiclayer was dried over Na₂SO₄ and concentrated to give the crude product,which was purified by flash column chromatography to yield the titlecompound (193.4 mg) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δppm 1.88-1.89 (m, 4H), 2.05-2.09 (m, 4H), 2.60-2.90 (m, 4H), 3.30-3.40(m, 4H), 3.55-3.57 (m, 1H), 3.68-3.74 (m, 2H), 3.85-3.95 (m, 2H),4.38-4.51 (m, 4H), 5.91 (dd, J=6.0, 4.4 Hz, 1H), 7.01 (m, 1H), 7.25-7.31(m, 2H); ESI-MS m/z [M+H]⁺ 474.3.

EXAMPLE 150(S)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-1-one

To a solution of(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine(2.5 g, 5.85 mmol) in dioxane:acetone (105 ml, 1.5:1) was addedpropionic anhydride (7 mL, 3.76 mmol) and Pd/C (400 mg, 3.76 mmol);then, the reaction was stirred at 60° C. and under H₂ atmosphere (345kPa) for 72 h. The mixture was filtered through a pad of Celite™ andwashed with EtOAc. The reaction solution was diluted with EtOAc (50 mL)and poured into sat. aqueous NaHCO₃ (50 mL) then washed with brine (2×30mL). The organic layer was dried over Na₂SO₄ and concentrated to givethe crude product, which was purified by flash column chromatography togive the title compound (125 mg) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ ppm 0.97-1.03 (m, 3H), 1.87-2.04 (m, 6H), 2.15-2.25 (m, 1H),2.40-2.43 (m, 2H), 2.58-2.60 (m, 1H), 2.69-2.73 (m, 1H), 2.88 (q, J=9.6Hz, 2H), 3.30-3.34 (m, 2H), 3.50-3.60 (m, 1H), 3.70-3.74 (m, 2H),3.84-3.90 (m, 2H), 4.35-4.60 (m, 4H), 5.88-5.92 (m, 1H), 6.98-7.02 (m,1H), 7.27-7.30 (m, 2H); ESI-MS m/z [M+H]⁺ 488.3.

EXAMPLE 1511-(3-((3,3-difluorocyclobutyl)amino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

To a pressure reactor charged with a yellow-orange solution ofN-(3,3-difluorocyclobutyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine(250 mg, 0.559 mmol) in acetone (10 mL) and dioxane (10 mL) was addedpalladium, 10 wt % on activated carbon (23.8 mg, 0.223 mmol) as a slurryin dioxane (2 mL) under nitrogen. Next, acetic anhydride (0.525 mL, 5.59mmol) was added at 23° C. The mixture was stirred under hydrogen at 310kPa for 45 h at 45° C. The reaction mixture was filtered throughCelite™, rinsed with dioxane, and concentrated via rotary evaporation.The crude material was purified via medium pressure chromatography usinga gradient eluant of 30% to 100% EtOAc in heptane on a 80 g silica gelcolumn (Single Step™) to give the title compound (145 mg, 52.6%) as ayellow solid. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers) δ ppm1.80-1.95 (m, 2H), 2.03-2.08 (m, 2H), 2.0 (s, 1.3H), 2.09 (s, 1.7H),2.60 (t, J=5.6 Hz, 0.9H), 2.67-2.80 (m, 3.1H), 2.83-2.98 (m, 4H),3.31-3.38 (m, 2H), 3.71 (dt, J=11.2, 5.6 Hz, 2H), 4.14-4.27 (m, 1H),4.42 (s, 1.1H), 4.45 (s, 0.9H), 4.53 (tt, J=8.2, 3.8 Hz, 1H), 6.46 (dd,J=14.6, 6.8 Hz, 1H), 6.98-7.06 (m, 1H), 7.25-7.36 (m, 2H); ESI-MS m/z493.9 (M+H)⁺ 493.9.

EXAMPLE 152N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 11 usingN-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineto give the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.55-1.75(m, 2H), 1.84-1.96 (m, 2H), 1.96-2.14 (m, 4H), 2.18-2.32 (m, 2H), 2.75(t, J=5.9 Hz, 2H), 2.84-2.95 (m, 2H), 2.95-3.03 (m, 3H), 3.26-3.33 (m,2H), 3.45 (t, J=5.9 Hz, 2H), 4.16 (s, 2H), 4.30-4.44 (m, 1H), 4.52 (tt,J=8.1, 3.8 Hz, 1H), 6.12 (d, J=7.8 Hz, 1H), 6.95-7.08 (m, 1H), 7.23-7.37(m, 2H); ESI-MS m/z (M+H)⁺ 494.0.

EXAMPLE 153(R)-1-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to 149 using(R)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amineto give the title compound as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δppm 1.82-1.86 (m, 1H), 2.20 (s, 3H), 2.33-2.36 (m, 1H), 2.59-2.66 (m,4H), 2.79 (m, 2H), 3.05-3.15 (m, 4H), 3.63 (s, 1H), 3.69-3.72 (m, 2H),3.85-3.88 (m, 2H), 3.95-3.99 (m, 2H), 4.46-4.64 (m, 3H), 4.87-4.90 (m,1H), 6.79-6.90 (m, 2H), 7.39-7.41 (m, 1H); ESI-MS m/z [M+H]⁺ 473.1.

EXAMPLE 154(S)-1-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to 149 using(S)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amineto give the title compound as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.82-1.86 (m, 1H), 2.20 (s, 3H), 2.33-2.36 (m, 1H),2.59-2.66 (m, 4H), 2.79 (dt, J=21.6, 5.6 Hz, 2H), 3.05-3.15 (m, 4H),3.63 (s, 1H), 3.69-3.72 (m, 2H), 3.85-3.88 (m, 2H), 3.98-4.00 (m, 2H),4.48-4.64 (m, 3H), 4.88-4.92 (m, 1H), 6.82 (t, J=9.6 Hz, 1H), 6.84 (t,J=12.8 Hz, 1H), 7.39 (q, J=7.2 Hz, 1H); ESI-MS m/z [M+H]⁺ 473.1.

EXAMPLE 155(S)-1-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-1-one

The title compound was prepared in a manner similar Example to 150 using(S)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amineto give the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm 1.18 (q, J=7.2 Hz, 3H), 1.75-1.85 (m, 1H), 2.25-2.46 (m, 3H),2.55-2.65 (m, 4H), 2.75-2.80 (m, 2H), 3.00-3.10 (m, 4H), 3.59-3.70 (m,4H), 3.87-3.90 (m, 2H), 3.96-3.98 (m, 2H), 4.46-4.62 (m, 3H), 4.85-4.95(m, 1H), 6.75-6.90 (m, 2H), 7.35-7.45 (m, 1H); ESI-MS m/z [M+H]⁺ 487.3.

EXAMPLE 1561-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone

The title compound was prepared in a manner similar to Example 120 using4-(2,4-difluorophenoxy)piperidine, HCl to give the title compound as acolorless film. ¹H NMR (500 MHz, methanol-d4) δ ppm 0.85-0.93 (m, 1H),1.25 (d, J=6.4 Hz, 6H), 1.95 (ddd, J=12.1, 8.2, 3.7 Hz, 2H), 2.09-2.17(m, 2H), 2.20 (d, J=8.8 Hz, 3H), 2.74 (t, J=5.9 Hz, 1H), 2.84 (t, J=5.6Hz, 1H), 2.92-3.02 (m, 2H), 3.35 (dd, J=8.3, 3.9 Hz, 2H), 3.81 (t, J=5.6Hz, 1H), 3.86 (t, J=5.9 Hz, 1H), 4.12-4.21 (m, 1H), 4.46 (dd, J=7.1, 3.7Hz, 1H), 4.54 (s, 2H), 6.85-6.91 (m, 1H), 6.96-7.02 (m, 1H), 7.18 (td,J=8.8, 5.4 Hz, 1H); ESI-MS m/z [M+H]⁺ 446.90.

The compounds of the invention can be administered alone or in the formof a pharmaceutical composition. In practice, the compounds of theinvention are usually administered in the form of pharmaceuticalcompositions, that is, in admixture with at least one pharmaceuticallyacceptable excipient. The proportion and nature of any pharmaceuticallyacceptable excipient(s) are determined by the properties of the selectedcompound of the invention, the chosen route of administration, andstandard pharmaceutical practice.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising: a compound of invention and at least onepharmaceutically acceptable excipient.

In effecting treatment of a patient in need of such treatment, acompound of the invention can be administered in any form and routewhich makes the compound bioavailable. The compounds of the inventioncan be administered by a variety of routes, including orally, inparticularly by tablets and capsules. The compounds of the invention canbe administered parenteral routes, more particularly by inhalation,subcutaneously, intramuscularly, intravenously, intraarterially,transdermally, intranasally, rectally, vaginally, occularly, topically,sublingually, and buccally, intraperitoneally, intraadiposally,intrathecally and via local delivery for example by catheter or stent.

One skilled in the art can readily select the proper form and route ofadministration depending upon the particular characteristics of thecompound selected, the disorder or condition to be treated, the stage ofthe disorder or condition, and other relevant circumstances. Thepharmaceutical compositions of the invention may be administered to thepatient, for example, in the form of tablets, capsules, cachets, papers,lozenges, wafers, elixirs, ointments, transdermal patches, aerosols,inhalants, suppositories, solutions, and suspensions.

The pharmaceutical compositions of the present invention are prepared ina manner well known in the pharmaceutical art and include at least oneof the compounds of the invention as the active ingredient. The amountof a compound of the present invention may be varied depending upon itsparticular form and may conveniently be between 1% to about 50% of theweight of the unit dose form. The term “pharmaceutically acceptableexcipient” refers to those typically used in preparing pharmaceuticalcompositions and should be pharmaceutically pure and non-toxic in theamounts used. They generally are a solid, semi-solid, or liquid materialwhich in the aggregate can serve as a vehicle or medium for the activeingredient. Some examples of pharmaceutically acceptable excipients arefound in Remington's Pharmaceutical Sciences and the Handbook ofPharmaceutical Excipients and include diluents, vehicles, carriers,ointment bases, binders, disintegrates, lubricants, glidants, sweeteningagents, flavoring agents, gel bases, sustained release matrices,stabilizing agents, preservatives, solvents, suspending agents, buffers,emulsifiers, dyes, propellants, coating agents, and others.

The present pharmaceutical compositions are preferably formulated in aunit dose form, each dose typically containing from about 0.5 mg toabout 100 mg of a compounds of the invention. The term “unit dose form”refers to a physically discrete unit containing a predetermined quantityof active ingredient, in association with a suitable pharmaceuticalexcipient, by which one or more is used throughout the dosing regimen toproduce the desired therapeutic effect. One or more “unit dose form” maybe taken to affect the treatment dosage on a daily schedule.

In one particular variation, the composition is a pharmaceuticalcomposition adapted for oral administration, such as a tablet or acapsule or a liquid formulation, for example, a solution or suspension,adapted for oral administration. In still another particular variation,the pharmaceutical composition is a liquid formulation adapted forparenteral administration.

Compounds of the present invention are modulators of GPR6, specifically,antagonists or inverse agonists, and as such are useful in the treatmentand prevention of conditions associated with GPR6. As mentioned above,the major striatal targets of dopaminergic innervation reside in themedium spiny neurons (MSNs) of the striatopallidal (indirect) andstriatonigral (direct) output pathways. The MSNs of the direct outputpathway express D1 dopamine receptors whereas those in the indirectpathway express D2 receptors. GPR6 is enriched in D2 receptor expressingMSNs in the striatum where GPR6 activity is functionally opposed to D2receptor signaling. Antagonism or inverse agonism of Gs coupled GPR6decreases cAMP in MSNs and provides a functional alternative to dopaminemediated activation of D2 receptors.

Antagonism or inverse agonism of Gs coupled GPR6 provides a functionalalternative to dopamine mediated activation of D2 receptors. As such,compounds that modulate the activity of GPR6 are useful for treating ina variety of neurological and psychiatric disorders. For examplemovement disorders including Parkinson's disease and Huntington'sdisease either alone or in combination with other agents are approvedfor the treatment of Parkinson's disease including L-DOPA, dopaminergicagonists, MAO B inhibitors, DOPA decarboxylase inhibitors and C(O)MTinhibitors. Other disease indications that could be treated bymodulation of GPR6 include drug addiction and eating disorders,cognitive disorders, schizophrenia, bipolar disorders, and depression.

In another embodiment, the invention provides methods of treatingconditions associated with GPR6, comprising: administering to a patientin need thereof an effective amount of a compound of the invention. Inanother embodiment, a compound of the invention is provided for use as amedicament. The invention also provides the use of a compound of theinvention, including the use for the manufacture of a medicament, totreat the conditions associated with GPR6 described herein. Thecompounds of the present invention are useful as GPR6 modulators for avariety of subjects (e.g., humans, non-human mammals and non-mammals).

As used herein terms “condition,” “disorder,” and “disease” relate toany unhealthy or abnormal state. The term “conditions associated withGPR6” includes conditions, disorders, and diseases in which themodulators of GPR6 provides a therapeutic benefit, such as Parkinson'sdisease, levodopa induced dyskinesias, and Huntington's disease, drugaddiction, eating disorders, cognitive disorders, schizophrenia, bipolardisorders, and depression.

The terms “treat,” “treatment,” and “treating” include improvement ofthe conditions described herein. The terms “treat,” “treatment,” and“treating” include all processes providing slowing, interrupting,arresting, controlling, or stopping of the state or progression of theconditions described herein, but does not necessarily indicate a totalelimination of all symptoms or a cure of the condition. The terms“treat,” “treatment,” and “treating” are intended to include therapeutictreatment of such disorders. The terms “treat,” “treatment,” and“treating” are intended to include prophylactic treatment of suchdisorders.

As used herein the terms “patient” and “subject” includes humans andnon-human animals, for example, mammals, such as mice, rats, guineapigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. Theterm also includes birds, fish, reptiles, amphibians, and the like. Itis understood that a more particular patient is a human. Also, moreparticular patients and subjects are non-human mammals, such as mice,rats, and dogs.

As used herein, the term “effective amount” refers to the amount ofcompound of the invention which treats, upon single or multiple doseadministration, a patient suffering from the mentioned condition. Aneffective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount, the dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto, the species of patient, its size, age, and general health; thespecific condition, disorder, or disease involved; the degree of orinvolvement or the severity of the condition, disorder, or disease, theresponse of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances. An effective amount of the present invention, thetreatment dosage, is expected to range from 1 mg to 200 mg. Specificamounts can be determined by the skilled person. Although these dosagesare based on an average human subject having a mass of about 60 kg toabout 70 kg, the physician will be able to determine the appropriatedose for other patients.

The pathological hallmark of Parkinson disease (PD) is neuronal cellloss within the substantia nigra. Degeneration of the nigrostriatalpathway causes reduction in the striatal concentration of dopamine whichresults in motor and nonmotor clinical manifestations. Many Parkinson'sdisease patients are treated with levodopa, a prodrug for dopamineLevodopa has common serious side effects including induced dyskinesia(LID), impulsive control disorders (ICD), psychotic symptoms and sleepdisturbances. LID is progressive (90% of PD patients develop LID within10yrs). Irreversible adaptations occur in D1 receptor signaling in MSNsin rodent models of LID including reduced desensitization leading tohypersensitivity in the direct pathway. Genetic inactivation of D1 butnot D2 receptors abolishes LID in mice. However blockade of D1 receptorsignaling does not affect the antiparkinsonian efficacy of L-DOPA.

In a particular embodiment, the present invention provides a method oftreating Parkinson's disease comprising: administering to a patient inneed thereof an effective amount of a compound of the invention. Thatis, the invention also provides the use of a compound of the invention,including the use for the manufacture of a medicament, to treatParkinson's disease.

The compounds of the invention may be combined with one or more otherpharmacologically active compounds or therapies for the treatment of oneor more disorders, diseases or conditions for which GPR6 is indicatedmay be administered simultaneously, sequentially or separately incombination with one or more compounds or therapies for treatingParkinson's disease, levodopa induced dyskinesias, and Huntington'sdisease, drug addiction, eating disorders, cognitive disorders,schizophrenia, bipolar disorders, and depression. Such combinations mayoffer significant therapeutic advantages, including fewer side effects,improved ability to treat underserved patient populations, orsynergistic activity. In particular, the compounds of the invention maybe administered with levodopa for treating Parkinson's disease. Thepresent invention provides a method treating Parkinson's diseasecomprising: administering to a patient in need thereof an effectiveamount of a compound of the invention in combination with levadopa. Theinvention also provides the use of a compound of the invention incombination with levadopa, including the use for the manufacture of amedicament, to treat Parkinson's disease.

The activity of compounds as GPR6 modulators may be determined by avariety of methods, including in vitro and in vivo methods.

EXAMPLE A.1

Inhibition of cAMP Activity of GPR6 In Vitro Assay

This cell based assay measures the ability of compounds to inhibit theconstitutive cAMP activity of GPR6 receptor expressed in CHO-K1 cells.CHO cells were stably expressed with GPR6 receptor, whose expression iscontrolled by a tetracycline inducable element. The cells were culturedin medium containing F12K, 10% FBS, 1% Penn/Strep, 200 ug/mL Hygromycin.GPR6 receptor expression was induced for 20 hrs with 1 μg/ml doxycycline(sigma D9891) in growth media. After addition of doxycycline cells wereplated at a density of 250-500 cells per well in half-volume black clearbottom plates (Costar) and place in an incubator (37°, 5% C(O)₂) for 20hours prior to cAMP assays.

Culture media was removed from cells and they were washed with 50 μL ofRinger's Buffer (MgCl₂ 0.047 mg/mL, NaH₂PO₄ 0.18 mg/mL, Na₂HPO₄ 0.1mg/mL, KCl 0.34 mg/mL, NaHC(O)₃ 1.26 mg/mL, D-glucose 1.8 mg/mL, NaCl 7mg/mL; pH=7.4). Compounds suspended in DMSO were diluted in Ringer'sBuffer containing 0.5% fatty acid free BSA and incubated on cells for 45min at 37° and 5% C(O)₂. After incubation cells were incubated for 10min at room temp with Eu-cAMP tracer solution from a Perkin Elmer LanceHTRF UltracAMP assay kit (TRF0264). Then ULight™-anti-cAMP solution fromthe Lance HTRF kit was added and incubated on a shaker at room temp for1 hour prior to HTRF detection in a BMG PolarStar Omega.

IC₅₀ curves were generated with a four-parameter logistic equation usingGraphPad Prism 5.03. Measured IC₅₀ value (μM) of example compounds inthis assay is provided in the table below.

EXAMPLE A.2

Inhibition of cAMP Activity of GPR6 In Vitro Assay

This cell based assay measures the ability of compounds to inhibit theconstitutive cAMP activity of GPR6 receptor expressed in CHO-K1 cells.CHO cells were stably expressed with GPR6 receptor, whose expression iscontrolled by a tetracycline inducable element. The cells were culturedin medium containing F12K, 10% FBS, 1% Penn/Strep, 200 ug/mL Hygromycin.GPR6 receptor expression was induced for 20 hrs with 2 μg/ml doxycycline(sigma D9891) in growth media. After addition of doxycycline cells wereplated at a density of 450-750 cells per well in 96-well half-volumeblack tissue culture plates (Costar) and placed in an incubator (37°, 5%CO₂) for 20 hours prior to cAMP assays.

Culture media was removed from cells and they were washed with 50μL/well of Ringer's Buffer (MgCl₂ 0.047 mg/mL, NaH₂PO₄ 0.18 mg/mL,Na₂HPO₄ 0.1 mg/mL, KCl 0.34 mg/mL, NaHCO₃ 1.26 mg/mL, D-glucose 1.8mg/mL, NaCl 7 mg/mL; pH=7.4). Compounds suspended in DMSO were dilutedin Ringer's Buffer containing 0.5% fatty acid free BSA plus 300 μM IBMXand incubated on cells for 45 min at 37° and 5% CO₂. After incubationcells were incubated for 10 min at room temp with Eu-cAMP tracersolution from a Perkin Elmer Lance HTRF Ultra cAMP assay kit (TRF0263).Then ULight™-anti-cAMP solution from the Lance HTRF kit was added andincubated on a shaker at room temp for 1 hour prior to HTRF detection ina Perkin Elmer Envision plate reader.

IC₅₀ curves were generated with a four-parameter logistic equation usingGraphPad Prism 5.03. Measured IC₅₀ value (μM) of example compounds inthis assay is provided in the Table 1 below.

TABLE 1 Ex. A.1 IC₅₀ A.2 IC₅₀ 1 340.2 2 71.5 3 61.8 4 29.8 5 17.9 6 55.27 86.6 8 16.8 9 210.6 10 17.3 11 95.6 12 13 14 62.6 15 14.9 16 19.5 1718 18 38.7 19 105 20 122 21 149 22 78.1 23 391 24 129.2 25 26 27 28 29178 30 87 31 208 32 76 33 52 34 68 35 88 36 98 37 91 38 85 39 126 40 25941 212.2 42 193.3 43 115.5 44 62.5 45 74.1 46 35 47 24.6 49 9.1 50 79.551 6.6 52 73.2 53 95 54 59.3 55 109.6 56 179.4 57 93.5 58 26.6 59 49.760 >1000 61 131.7 62 69.2 63 37.8 65 66 145 67 9.4 68 15.2 69 26.5 7017.1 71 8.5 72 23.7 73 16.6 74 140.2 75 30.3 76 13.4 77 19.7 78 8.8 799.8 80 24.9 81 59.5 82 73.7 83 13.8 84 90.1 85 10.4 86 13.7 87 13.8 8832.7 89 90 91 11.5 92 12 93 13.8 94 19.9 95 32.5 96 26.9 97 163 98 110.699 8.3 100 57.2 101 78.8 102 111 103 64 104 105 106 107 24.9 108 31.4109 23.2 110 22.1 111 23 112 10.4 113 20.9 114 18.5 115 23.9 116 199.7117 27.4 118 11.4 119 23.6 120 249.8 121 341.5 122 247 123 187.7 12443.2 125 200.2 126 107.1 127 >1000 128 55 129 62 130 319.3 131 27.6 132129.5 133 74.8 134 27 135 43.7 136 27.9 137 30.9 138 >1000 139 219.8 140122 141 33.7 142 113.5 143 29 144 61.5 145 185.9 146 362.9 147 603.9 14878 149 58.7 150 39.2 151 35.9 152 49.3 153 63.2 154 97.8 155 59.1 1569.5

EXAMPLE B

Haloperidol-Induced Catalepsy—In Vivo Rodent Parkinson's Disease Model

The motor symptoms of Parkinson's disease include akinesia,bradykinesia, rigidity, tremor and postural abnormalities and areassociated with the loss of nigral dopaminergic cells and a decline instriatal dopamine levels. Administration of haloperidol to rodents leadsto a transient parkinsonian-like state that is reversed by theadministration of L-Dopa (Duty, S.; Jenner, P. Br. J. Pharmacol. (2011),164, 1357-1391) and other drugs that have been clinically validated forthe treatment of Parkinson's disease. Haloperidol antagonizes dopamineD2 and, to a lesser extent, D1 receptors in medium spiny neurons thatcomprise the indirect and direct pathways of the motor circuitrespectively. The resultant block of striatal dopamine transmissionresults in abnormal downstream firing within the basal ganglia circuitsthat is manifest as symptoms of muscle rigidity and catalepsy. Catalepsyhas been postulated to reflect the clinical features of Parkinson'sdisease, whereby patients experience an inability of to initiatemovements.

Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175-200g are used. Alternatively, male C57B16 mice weighing 25-35 g were used.The cataleptic state was induced by the subcutaneous administration ofthe dopamine receptor antagonist haloperidol (0.3 mg/kg, sc), 90 minbefore testing the animals on the vertical grid test. For this test, therats or mice were placed on the wire mesh cover of a 25 cm×43 cmplexiglass cage placed at an angle of about 70 degrees with the benchtable. The subject was placed on the grid with all four legs abductedand extended (“frog posture”). The use of such an unnatural posture isessential for the specificity of this test for catalepsy. The time spanfrom placement of the paws until the first complete removal of one paw(descent latency) was measured maximally for 120 sec for rats. For mice,the front paws of a mouse was placed on a horizontal metal bar raised 2″above a Plexiglas platform and time was recorded for up to 30 secondsper trial. The test ended when the animal's front paws returned to theplatform or after 30 seconds. The test was repeated three times and theaverage of the three trials was reported as the intensity index ofcatalepsy.

Catalepsy was measured 30 min, 120 min, and/or 240 min after dosing thesubjects a 0.3 mg/kg i.p. dose of haloperidol along with the GPR6modulator test compound. Test compound plasma and brain levels weredetermined by collected tissue samples at the end of the experiment,which was either at the 120 or 240 min time point. A representativenumber of compounds of the invention were administered in a dose rangefrom 0.1 to 100 mg/kg i.p, sc or po in conjunction with haloperidol. TheA2a antagonist KW6002 (istradefylline) was dosed at 0.6 mg/kg i.p. as apositive control.

Measured % reversal of example compounds in this assay is provided inthe Table 2 below.

TABLE 2 Dose % reversal Ex. Species (mpk) Route 30 min 120 min 47 Rat 30i.p. 75.7* 82.1* 10 i.p. 83.4* 76.5* 1 i.p. 39.1 57.9* 0.1 i.p. −5.727.3 *significantly different than vehicle contol, one-way ANOVA withBonferroni's multiple test correction.

EXAMPLE C

6-Hydroxydopamine Lesion Model—In Vivo Rodent Parkinson's Disease Model

Adult female rats (10) were first assessed for pre-surgery motoractivity using an automated activity tracking system that records beambreaks across the testing arena floor. Beam breaks were summed over thefirst 3 hours after the animals were placed into the arena and recordedas activity counts. To selectively damage dopaminergic nerve terminalsin the striatum, 20 μg of the 6-hydroxydopamine was injected directlyinto the striatum bilaterally (i.e., on both sides of the brain). After4 weeks of recovery, the rats were again tested for motor activity, anda significant reduction in activity counts was observed. Vehicle and thecompound of Example 47 (0.5% methylcellulose) was orally dosed at 0.1,1.0, or 10 mg/kg in a cross-over study design (5-10 day wash outperiod), and after dosing activity counts were measured for 3 hours. Atthe end of the study period, when each animal had received eachtreatment once, the data were analyzed. The activity counts (standarderror of the mean) for the group pre-surgery and post-surgery and fortreated and vehicle control were determined and are provide in Table 3below:

TABLE 3 Treatment Group Mean S.E.M Pre-Surgery 12171  1601 Vehicle 7253768 0.1 mg/kg 11422* 1071 1.0 mg/kg 15334* 2013  10 mg/kg 19368* 1410*significantly different than vehicle contol, one-way ANOVA withBonferroni's multiple test correction.

1-15. (canceled)
 16. The compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein R₁ is selectedfrom the group consisting of C₃₋₈ cycloalkyl optionally substituted with1 to 3 substituents independently selected from the group consisting ofC₁₋₄ alkoxy, halo, hydroxy, and C₁₋₄ alkyl optionally substituted withC₁₋₄ alkoxy, halo, and hydroxy; C₃₋₆ heterocyclyl optionally substitutedon ring carbons with 1 to 4 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₇ amido,amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, C₃₋₈cycloalkoxy, halo, hydroxy, nitro, oxo, and phenyl optionallysubstituted with 1 to 5 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amino, C₁₋₈alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxy, nitro, andtrifluoromethyl and optionally substituted on any ring nitrogen with asubstituent independently selected from the group consisting of C₁₋₄alkyl, C₃₋₈ cycloalkyl, C₃₋₆ heterocyclyl, C₁₋₁₀ heteroaryl, and phenyloptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amino, C₁₋₈alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxy, nitro, andtrifluoromethyl; C₆₋₁₀ aryl optionally substituted with 1 to 5substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, amino, C₁₋₈ alkylamino, C₁₋₉ amide,C₁₋₇ amido, C₁₋₅ oxycarbonyl, C₁₋₅ carbonyloxy, C₁₋₈ sulfonyl, C₁₋₅carbamoyl, C₁₋₆ sulfonylamido, aminosulfonyl, C₁₋₁₀ aminosulfonyl, C₁₋₅ureido, trifluoromethyl, trifluoromethoxy, cyano, halo, and hydroxy; andC₁₋₁₀ heteroaryl optionally substituted with 1 to 3 substituents oncarbon independently selected from the group consisting of amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halo, hydroxy,oxo, trifluoromethyl, and trifluoromethoxy and optionally substituted ona ring nitrogen with C₁₋₄ alkyl; X₁ is N and X₂ is CH; or X₁ is CH andX₂ is N; or X₁ is N and X₂ is N; when X₁ is N, Z is selected from thegroup consisting of C₁₋₆ alkylene, C₁₋₆ haloalkylene, —C(O)—, and—S(O)₂—; when X₁ is CH, Z is selected from the group consisting of C₁₋₆alkylene, C₁₋₆ haloalkylene, —O—, —C(O)—, —NH—, —S—, —S(O)—, and—S(O)₂—; q is 0, 1, or 2; s is 0, 1, or 2; R₂ is −OR₅ or —NR₆R₇; each R₃is independently selected from the group consisting of C₁₋₆ alkyl, C₃₋₈cycloalkyl, and trifluoromethyl; p is 0, 1, or 2; each R₄ isindependently selected from the group consisting of C₁₋₆ alkyl, hydroxy,and halo; r is0 or 1; R₅ is selected from the group consisting of C₁₋₆alkyl and C₃₋₈ cycloalkyl; R₆ is selected from the group consisting ofhydrogen and C₁₋₆ alkyl; R₇ is selected from the group consisting ofC₁₋₆ alkyl optionally substituted with 1 to 7 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, amino,C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo,hydroxy, C₃₋₆ heterocyclyl optionally substituted on any ring nitrogenby C₁₋₄ alkyl, C₁₋₁₀ heteroaryl, and phenyl optionally substituted with1 to 5 substituents independently selected from the group consisting ofC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl,cyano, halo, hydroxy, nitro, and trifluoromethyl; C₃₋₈ cycloalkyl; C₆₋₁₀aryl optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halo, hydroxy, amino, trifluoromethyl, and trifluoromethoxy; C₁₋₁₀heteroaryl optionally substituted with 1 to 3 substituents on carbonindependently selected from the group consisting of amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halo, hydroxy,oxo, trifluoromethyl, and trifluoromethoxy and optionally substituted ona ring nitrogen with C₁₋₄ alkyl; and C₃₋₆ heterocyclyl optionallysubstituted on ring carbons with 1 to 4 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halo, andhydroxy and optionally substituted on any ring nitrogen with C₁₋₄ alkyl;X₅ is selected from the group consisting of CH and CR₄, and X₆ isselected from the group consisting of NH and N—CH₂-(phenyl optionallysubstituted with 1 to 5 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amino, C₁₋₈alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxy, nitro, andtrifluoromethyl); or X₅ is selected from the group consisting of NH andN—CH₂-(phenyl optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₉ amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halo,hydroxy, nitro, and trifluoromethyl) and X₆ is selected from the groupconsisting of CH and CR₄.
 17. The compound or pharmaceuticallyacceptable salt according to claim 16, wherein X₁ is CH and X₂ is N. 18.The compound or pharmaceutically acceptable salt according to claim 16,wherein X₁ is N and X₂ is N.
 19. The compound or pharmaceuticallyacceptable salt according to claim 16, wherein R₁ is C₆₋₁₀ aryloptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ thioalkoxy,amino, C₁₋₈ alkylamino, C₁₋₉ amide, C₁₋₇ amido, C₁₋₅ oxycarbonyl, C₁₋₅carbonyloxy, C₁₋₈ sulfonyl, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido,aminosulfonyl, C₁₋₁₀ aminosulfonyl, C₁₋₅ ureido, trifluoromethyl,trifluoromethoxy, cyano, halo, and hydroxy.
 20. The compound orpharmaceutically acceptable salt according to claim 16, wherein Z isC₁₋₆ alkylene.
 21. The compound or pharmaceutically acceptable saltaccording to claim 16, wherein Z is C₁₋₆ haloalkylene.
 22. The compoundor pharmaceutically acceptable salt according to claim 16, wherein Z is—O—.
 23. The compound or pharmaceutically acceptable salt according toclaim 16, wherein Z is —C(O)—.
 24. The compound or pharmaceuticallyacceptable salt according to claim 16, wherein R₂ is —NR₆R₇.
 25. Thecompound or pharmaceutically acceptable salt according to claim 24,wherein X₅ is selected from the group consisting of CH and CR₄ and X₆ isNH.
 26. The compound or pharmaceutically acceptable salt according toclaim 24, wherein X₅ is NH and X₆ is selected from the group consistingof CH and CR₄.
 27. The compound or pharmaceutically acceptable saltaccording to claim 24, wherein X₅ is selected from the group consistingof CH and CR₄, and X₆ is N—CH₂-(phenyl optionally substituted with 1 to5 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₉ amino, C_(1—)g alkylamino, C₁₋₅ oxycarbonyl,cyano, halo, hydroxy, nitro, and trifluoromethyl).
 28. The compound orpharmaceutically acceptable salt according to claim 24, wherein X₆ isselected from the group consisting of CH and CR₄, and X₅ isN—CH₂-(phenyl optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, C₁,₉ amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halo,hydroxy, nitro, and trifluoromethyl).
 29. The compound according claim16, which is selected from the following compounds:6-benzyl-N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;6-benzyl-N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;(S)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;(R)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;(S)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;(R)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;4-((1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile;(S)-6-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;6-benzyl-3-(4-((2-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;6-benzyl-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;6-benzyl-N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;6-benzyl-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;6-benzyl-N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;6-benzyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;6-benzyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;6-benzyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;6-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;4-((1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile;and a pharmaceutically acceptable salt of any one of the aforementionedcompounds.
 30. The compound according to claim 16, which is selectedfrom the following compounds:3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile;N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;(S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine;3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile;3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;N-(tert-butyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine;and a pharmaceutically acceptable salt of any one of the aforementionedcompounds.